288A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n POSTER SESSION 908 Basic Aspects of Thrombosis and Hemostasis Sunday, March 12, 2006, 9:00 a.m.-12:30 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 908-159 Pharmacogenetic Warfarin-Dosing Algorithm Is Substantially Improved When Both VKORC1 and CYP2C9 Gene Variants Are Considered Benjamin D. Horne, Jeffrey L. Anderson, Joseph B. Muhlestein, Robert R. Pearson, Heidi Thomas, Brent C. James, Chrissa P. Mower, John F. Carlquist, LDS Hospital, Salt Lake City, UT, University of Utah, Salt Lake City, UT Background: Warfarin therapy is the standard of care for outpatient anticoagulation, but wide variability in patient response complicates its use. Patient response to warfarin is in part determined by its metabolism rate modulated by variations in the cytochrome P450 (CYP) 2C9 gene. However, the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene has recently been proposed to also be important. Methods: Patients (N=202) with atrial ﬁbrillation or deep vein thrombosis were enrolled if they met the stable warfarin dose criteria of >1 month on the same dose with an international normalized ratio of 2.0-3.0. Patients were genotyped for the CYP2C9 *2 (C/T) and *3 (A/ C) and the VKORC1 C1173T single nucleotide polymorphisms (SNPs). Genotypes, age, sex, and weight were evaluated in linear regression for prediction of warfarin dose and regression �-coefﬁcients were used to develop a pharmacogenetic dosing algorithm. Results: Warfarin doses ranged from 5-70 mg/week. Compared to CYP2C9 *2*3 CCAA genotype (mean±SD dose 33±14 mg/week), lower warfarin dose was predicted by CTAA (27±12 mg/week, p=0.004), CCAC (23±12 mg/week, p<0.001), and CTAC (6±1 mg/week, p<0.001). Lower dose was also predicted by VKORC1 CT (29±11 mg/week, p<0.001) and TT (21±11 mg/week, p<0.001) compared to CC (38±16 mg/week). Along with age (p<0.001), sex (p=0.099), and weight (p=0.021), this model accounted for 45% of the variation in warfarin dose, with the CYP2C9 SNPs accounting for 18% and the VKORC1 SNP for 15%. This model’s predicted doses ranged from 7-56 mg/week and were correlated with actual dose at r=0.66 (p<0.001). For unobserved CYP2C9 genotypes, meta-analysis of published literature determined relative contributions to predicted warfarin dose. The model was used as the basis for a dose initialization and adjustment algorithm. Conclusions: CYP2C9 and VKORC1 genotypes were the dominant determinants of warfarin dose, with a predictive model accounting for almost half of the variation in patient warfarin doses. This pharmacogenetic warfarin-dosing algorithm should now be tested in a randomized clinical trial to evaluate the improvement in safety and efﬁcacy of warfarin initiation and maintenance therapy. 908-160 Inhalation of Combustion-derived Air Pollution Impairs Endogenous Fibrinolysis in Patients With Ischemic Heart Disease Nicholas L. Mills, Hakan Törnqvist, Manuel Gonzalez, Simon D. Robinson, Alexander E. Finlayson, William MacNee, Flemming R. Cassee, Anders Blomberg, Thomas Sandstrom, Nicholas A. Boon, Ken Donaldson, David E. Newby, The University of Edinburgh, Edinburgh, United Kingdom, Umeå University, Umeå, Sweden Background: Air pollution is associated with an increase in cardiovascular morbidity and mortality. In particular, trafﬁc-derived air pollution may be an important trigger for acute myocardial infarction. We investigated the effects of dilute diesel exhaust and concentrated ambient particle inhalation on ﬁbrinolytic function in patients with ischemic heart disease. Methods: Patients with stable ischemic heart disease were exposed to dilute diesel exhaust (300 µg/m3) or ﬁltered air for 1 hour (n=16) and to concentrated ambient particles (CAPs) or ﬁltered air for 2 hours (n=12) in a double blind randomised cross over study. Six hours following exposure, plasma ﬁbrinolytic markers were measured before and during unilateral intra-brachial bradykinin infusion. Results: There were no differences in plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) concentrations at 2, 6 and 24 hours following all exposures. Bradykinin caused a dose-dependent increase in plasma t-PA concentrations (p<0.001) that was suppressed following exposure to diesel exhaust (p<0.05; area under the curve decreased by 35%). Although there was a dose dependent increase in plasma t-PA release with bradykinin (p<0.001), this was unaffected by CAPs (135±33.5 µg/m3) or ﬁltered air. Atomic time of ﬂight mass spectrometry analysis of inhaled CAPs identiﬁed low levels of carbon and a primary constituent of sodium chloride. Conclusions: Inhalation of diesel exhaust impairs endogenous ﬁbrinolytic function in patients with ischemic heart disease. The equivalent mass of ambient particulate, low in combustion component, did not affect endothelial t-PA release. These ﬁndings provide a potential mechanism that links combustion-derived air pollution to the pathogenesis of atherothrombosis and acute myocardial infarction. 908-161 A Phase-I Study to Assess the Antithrombotic Properties of DU-176b: An Orally Active Direct Factor- Xa Inhibitor Mohammad Urooj Zafar, Juan Gaztanaga, Mauricio Velez, David Vorchheimer, Brian Choi, Juan Viles-Gonzalez, Pedro Moreno, Valentin Fuster, Juan Badimon, Mount Sinai School of Medicine, New York, NY Background: Tissue factor pathway inhibition is a new therapeutic target in atherothrombotic disease. Treatment with standard indirect factor Xa [FXa] inhibitors (i.e. heparin & warfarin) has shown to be effective but is complicated by bleeding and requires cumbersome monitoring. Injectable direct FXa inhibitors offer better safety with efﬁcacy comparable to current treatments. These beneﬁts could be extended to the ambulatory setting with an oral agent. We evaluate the antithrombotic effects of an oral direct FXa inhibitor DU-176b in a phase I human study. Methods: Healthy males (n=12, 28±6 years) received a single, 60mg dose of DU-176b. Antithrombotic effects were assessed by changes in thrombus size pre- and post-dose, using the Badimon chamber at venous and moderately stenosed arterial ﬂow conditions. Perfusion studies and measurements for anti-FXa activity and thrombin generation were performed pre-dose, and at 1.5-, 5- and 12-hours post-dose. Results:see table. Effect of DU-176b on Thrombus Formation and Clotting Parameters Anti-Thrombotic Effect 1.5 hour post-dose 5 hour post- dose 12 hour post- dose Venous Thrombosis (% reduction) 28% * 21% * 3% Arterial Thrombosis (% reduction) 26% * 17% * 3% Thrombin Generation-ETP (% reduction) 28% * 10% * -3% Anti-FXa Activity (IU/ml) 3.6 (±1.6) 1.6 (±0.3) 0.3 (±0.2) Drug Level (ng/ml) 240 (±54) 127 (±22) 37 (±10) Clotting Parameters Pre-dose 1.5 hour post- dose 5 hour post- dose 12 hour post- dose PT (seconds) 13.4 (±0.7) 20.3 (±1.9)* 17.5 (±1.5)* 14.7 (±0.7)* aPTT (seconds) 32.3 (±3.2) 41.1 (±5.4)* 37.8 (±3.9)* 33.6 (±3.1)* INR 1.1 (±0.1) 2.2 (±0.4)* 1.7 (±0.3)* 1.3 (±0.1)* Results for thrombus area and thrombin generation expressed as % reduction from pre- dose values. * Statistically signiﬁcant versus pre-dose values (p<0.05). Conclusion: DU-176b, an oral, direct FXa inhibitor, signiﬁcantly reduced thrombus formation (venous and arterial) and thrombin generation upto 5 hours post-dose. The antithrombotic effect mirrored changes in the clotting parameters, which could be used for monitoring in a clinical setting. The implications of TF pathway inhibition by DU-176b as a new therapeutic tool requires further study in larger clinical trials. 908-162 Platelet Aspirin Resistance in Patients With Coronary Artery Disease Is Rare at all Aspirin Doses When Measured by COX-1 Speciﬁc Assays Paul A. Gurbel, Kevin P. Bliden, Joseph DiChiara, Srivasavi Chaganti, Udaya S. Tantry, Sinai Center for Thrombosis Research, Baltimore, MD Background: Platelet aspirin resistance may be overestimated by measurements that are affected by pathways other than platelet COX-1. Using COX-1 speciﬁc methods we showed that aspirin resistance is rare in stent patients treated with 325mg aspirin. Methods: In a prospective, randomized, double-blind, double crossover study, we are evaluating aspirin dosing in patients (n=165) with stable coronary artery disease. Patients are randomized to a drug treatment sequence of 81, 162 and 325 mg/day for 4 weeks. 1,2 and 5 mM arachidonic acid (AA)-induced aggregation by light transmittance aggregometry (LTA), 1 mM AA-induced aggregation by thromboelastography (TEG) and urine 11-dehydro thromboxane (TxB2) were determined at the end of each treatment period. Resistance was deﬁned as >20% aggregation by LTA and >50% aggregation by TEG. The ﬁrst 56 pts. are reported. Results: Only one patient exhibited aspirin resistance at all the doses of aspirin as measured by 5 mM AA-induced LTA (Figure). 4% (81 mg), 6% (162mg) and 2% (325 mg) of patients were resistant to aspirin therapy by TEG. There was no correlation between urine TxB2 and AA-induced LTA and TEG. Conclusions: The prevalence of platelet aspirin resistance is rare among patients with stable coronary artery disease at all doses of aspirin when measured by COX-1 speciﬁc methods. Urinary thromboxane levels are not speciﬁc in determining platelet aspirin resistance and may result from non-platelet sources (COX-2). monitored ACC_2006_8_VascularDisease.indd 288 1/4/06 5:20:48 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 289A Vascular D isease, H ypertension, and P revention 908-163 Assessment of Coronary Red and White Thrombus by Optical Coherence Tomography Teruyoshi Kume, Takahiro Kawamoto, Takashi Akasaka, Eiji Toyota, Nozomi Watanabe, Renan Sukmawan, Yuji Kayama, Kiyoshi Yoshida, Kawasaki Medical School, Kurashiki, Japan Background: Recently, optical coherence tomography (OCT) has been proposed as a high-resolution imaging method. However, the OCT appearance of thrombi has not been well described. We sought to analyze the OCT characteristics of different types of coronary thrombi conﬁrmed at post mortem histological examination. Methods: We examined 108 coronary arterial segments of 40 consecutive human cadavers. OCT images of red and white thrombi were obtained and analyzed intensity property of both thrombi. Results: Red and white thrombi were found in 16 (17%) and 19 (18%) of the 108 arterial segments, respectively. Red thrombi were identiﬁed as high-backscattering protrusions inside the lumen of the artery, with signal-free shadowing in the OCT image. White thrombi were identiﬁed as low-backscattering projections in the OCT image. There were no signiﬁcant differences in the peak intensity of the OCT signal between red and white thrombi (130 ± 18 versus 145 ± 34, p=0.12). However the half attenuation width of the signal intensity curve, which was deﬁned as the distance from the peak intensity to its half intensity, was signiﬁcantly different between red and white thrombi (324 ± 50 versus 183 ± 42 µm, p<0.0001). Cutoff value of 250 µm in the half width of signal intensity attenuation can differentiate white thrombi from red thrombi with the sensitivity of 90% and the speciﬁcity of 88%. Conclusions: We present the ﬁrst detailed description of the characteristics of different types of coronary thrombi in OCT images. OCT may allow us not only to estimate plaque morphology but also to distinguish between red and white thrombi. 908-164 Genetic Polymorphisms on Platelet Glycoprotein Ia, Increase the Risk for Myocardial Infarction by Modifying Platelet Activation Charalambos Antoniades, Dimitris Tousoulis, Carmen Vasiliadou, Nikolaos Koumallos, Kyriakoula Marinou, Costas Tentolouris, Marina Toutouza, Gerasimos Siasos, Christos Pitsavos, Christodoulos Stefanadis, Athens University, A Cardiology Department, Athens, Greece Background Platelet membrane glycoprotein Ia (GPIa) has an important role in platelet activation during the acute phase of myocardial infarction (MI), as a receptor for collagen. Platelets activation during MI is characterized by both the release of soluble CD40-ligand (sCD40L) and P-selectin (P-Sel). Although silent genetic polymorphism C807T affects the platelet density of GPIa and G1648A determines the Bra/b platelet antigens, their role during MI is unknown. Methods: The study population consisted of 219 patients with ﬁrst event of premature MI and 387 healthy controls. A sub-population of 67 patients and 232 matched controls were recalled one year after the event, to participate in the follow-up study. Distribution of C807T polymorphism was determined by PCR and plasma sCD40L and P-Sel by ELISA. Results: The genotypes distribution were for 807TT/CT/CC: 34/112/73 in patients and 30/214/143 in controls (p<0.05) and for 1648GG/AG/AA: 161/50/8 in patients and 300/77/10 in controls (p=NS). The risk for MI in 807TT was 2.296(95%CI:1.187-4.440) p=0.014 after adjustment for potential confounders. During the acute phase of MI, plasma sCD40L and P-sel were higher in 807CT+TT (12.77±1.22pg/ml and 68.2±4.9ng/ ml respectively) compared to CC (7.12±0.93pg/ml and 39.9±3.67ng/ml respectively, p<0.01 for both). One year after the event, although sCD40L and P-sel were decreased in all genotypes, they remained higher in CT+TT (8.73±0.97pg/ml and 51.1±3.6ng/ml) compared to CC(4.35±0.93pg/ml and 37.2±2.6ng/ml respectively, p<0.01 for both). The increase of sCD40L and P-sel from rest (at one year) to the acute phase, was higher in CT+TT compared to CC (p<0.01). In healthy controls, sCD40L and P-selectin were not different in CC (4.19±0.48pg/ml and 31.1±3.1ng/ml respectively) compared to CT+TT (5.3±0.33pg/ml and 35.8±1.8 p=ns for both). Conclusions: Genetic polymorphism C807T on platelet glycoprotein Ia is a risk factor for premature MI, and it affects the release of sCD40L and P-selectin during the acute phase of MI, an effect sustained in the same patients one year after the event. Therefore C807T polymorphism may modify platelet activation, especially during the acute phase of myocardial infarction 908-165 Monitoring Platelet Inhibition After Clopidogrel With VerifyNow-P2Y12® Rapid Analyzer: The VERIfy Thrombosis risk ASsessment (VERITAS) Study Alex Malinin, Alex Pokov, Kenneth Schwartz, Dianne Schwartz, Malcolm Spergling, Anthony Defranco, Ehtisham Mahmud, Victor Serebruany, HeartDrug Research, Towson, MD, Edinger Research Center, Fauntain Valley, CA Background: Clopidogrel inhibits platelet P2Y12 ADP receptors, while ADP, as an inductor of aggregation, stimulate both P2Y12 and P2Y1 platelet receptors, leading to underestimation of clopidogrel efﬁcacy. However, despite therapy with clopidogrel some post stroke patients still experience recurrent cerebrovascular events suggesting persistent platelet activation. VerifyNow-P2Y12 assay directly measures the effects of clopidogrel on the P2Y12 receptor using a novel FDA approved cartridge. The platelet response to clopidogrel therapy was measured in subjects with multiple risk factors or history of vascular disease with the VerifyNow-P2Y12 assay in a prospective VERIfy Thrombosis risk ASsessment (VERITAS) study. Methods: 166 participants were enrolled in 4 participating sites, nineteen patients were excluded. Data from 147 participants were analyzed. Platelet function was assessed twice at baseline (before clopidogrel), and at 24 hours post-loading 450mg, or seven days after clopidogrel treatment (75mg/day). All participants received aspirin 81-325mg for at least two days before the study enrollment. The results are reported in P2Y12 Reaction Units (PRU) for the VerifyNow-P2Y12 assay and percent inhibition was calculated by dividing the post-dose by the pre-dose PRU. Results: Therapy with clopidogrel resulted in a 64.0 ± 25.3% reduction in platelet function (16.6-99.8% range). No one participant had PRU % inhibition less that 10% versus baseline. Distributions of PRU values for the VerifyNow-P2Y12 Assay show a clear separation from baseline to post-clopidogrel assay values despite high interindividual variability. Conclusion: VerifyNow-P2Y12 is a reliable, fast, and sensitive device suitable for monitoring of platelet inhibition after clopidogrel intake. Further studies in patients after coronary stenting, and post-stroke/TIA population are warranted. 908-166 Transient Coronary Occlusion Stimulates Platelet Deposition and Microvascular Dysfunction in Remote Regions of the Heart: Relation to Platelet Activation Status Jose A. Barrabes, David Garcia-Dorado, Maribel Mirabet, Luis Agullo, Jaume Figueras, Pilar Pizcueta, Jordi Soler-Soler, Hospital Vall d’Hebron, Barcelona, Spain Background: Acute coronary syndromes are associated with systemic platelet activation and with endothelial dysfunction, but the relations between these phenomena are not clear. We assessed the magnitude of platelet deposition and the changes in the coronary ﬂow reserve in remote regions of the heart after transient coronary occlusion, and their relation to platelet activation status. Methods: In 10 anesthetized pigs (series A), in which platelets had been labeled with 99mTc, the left anterior descending coronary artery (LAD) was injured and ligated for 48 min. After 2 h of reperfusion, the heart was excised and platelet content in a segment of the right coronary artery (RCA) and in nonischemic myocardium was counted. In 10 pigs (series B), the hyperemic response after a 25-s occlusion at the mid LAD was measured before and at several time points after ligating the RCA for 48 min. The percentage of circulating platelets expressing P-selectin was determined in both series by ﬂow cytometry. Results: In series A, platelet deposition averaged 12.3 ± 1.8 x 103/mm2 on the RCA and 14.2 ± 1.6 x 106/g in nonischemic myocardium, these values being correlated (r = 0.76). Platelet deposition on the RCA and in nonischemic myocardium were also associated with platelet content (r = 0.60 and 0.74, respectively), myeloperoxidase activity (r = 0.68 and 0.56) and infarct size (r = 0.66 and 0.72) in the reperfused zone, as well as with the percentage of P-selectin-positive platelets after reﬂow (r = 0.46 and 0.81). In series B, peak hyperemic response in the LAD at baseline was 285 ± 26% of the preocclusion value. Hyperemic response at the LAD was attenuated 15 min after releasing the RCA occlusion (82 ± 5% of the baseline value, P < 0.05), recovering thereafter (96 ± 11% after 1 h and 99 ± 9% after 3 h of reperfusion). The reduction in LAD hyperemic response early after reﬂow was associated with platelet P-selectin expression (r = 0.67, P = 0.03). Conclusions: Ischemic injury triggers a macro- and microvascular platelet deposition and a transient reduction in the coronary ﬂow reserve in remote zones of the heart, which are related to activation of circulating platelets. These ﬁndings may be relevant to patients with acute coronary syndromes. 908-167 Protease Activated Receptor-1 Activation Causes Platelet Independent Venoconstriction in Vivo in Man Ingibjorg J. Gudmundsdottir, David J. Webb, David E. Newby, Cardiovascular Sciences, University of Edinburgh, Edinburgh, United Kingdom Background: Protease-Activated Receptor type 1 (PAR-1) is a G-protein coupled receptor that mediates the majority of the cellular actions of thrombin in man. PAR-1 appears to regulate vasomotor control and platelet activation, although its effects have not previously been described in vivo in man. During inﬂammation, PAR-2 is up regulated and may modulate vascular responses. Methods: Dorsal hand vein diameter was assessed by the Aellig technique in 14 healthy volunteers. Norepinephrine (1-128 ng/min) maintained stable venoconstriction during PAR-1 agonist, SFLLRN (0.05-5 nmol/min), and PAR-2 agonist, SLIGKV (1.6, 16 and 160 nmol/min), infusions. The inﬂuence of platelet activation (Figure) was determined by co-infusing SFLLRN (0.05-15 nmol/min) with and without the GPIIb/IIIa antagonist tiroﬁban (125 ng/min). Results: SFLLRN and SLIKGV caused dose-dependent venoconstriction (n ≥ 6, p<0.001) and venodilatation (n=6, p=0.015) respectively. SFLLRN induced venoconstriction was unaffected by tiroﬁban co-infusion (n=6, p=ns). Vein patency was maintained at all times with no in situ thrombus formation. Conclusions: : PAR-1 and PAR-2 activation cause venoconstriction and venodilatation respectively in vivo in man. PAR-1 mediated venoconstriction is independent of platelet aggregation. We conclude that thrombin causes direct PAR-1 induced venoconstriction in man and that PAR mediated vasomotor responses may depend on the inﬂammatory state of the vasculature. ACC_2006_8_VascularDisease.indd 289 1/4/06 5:20:48 PM 290A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n 908-168 Impact of Enhanced Platelet Reactivity on Microvascular Reperfusion and Left Ventricular Remodeling in ST-segment Elevation Myocardial Infarction. Zenon Huczek, Janusz Kochman, Krzysztof J. Filipiak, Grzegorz J. Horszczaruk, Radoslaw Piatkowski, Marcin Grabowski, Marek Roik, Joanna Wilczynska, Bernhard Meier, Grzegorz Opolski, The Medical University of Warsaw, Warsaw, Poland, Swiss Cardiovascular Center, Bern, Switzerland Background: Platelet reactivity is believed to play an important role in both ischemic and reperfusion phase of myocardial infarction. We tried to determine whether measurement of platelet reactivity on admission allows identifying patients with increased risk of impaired microvascular reperfusion and left ventricular remodeling in ST-segment elevation myocardial infarction (STEMI) treated with primary angioplasty (PCI). Methods: Platelet reactivity was estimated on admission in 110 patients presenting with STEMI with the use of PFA-100 (Dade Behring®) as the time for ﬂowing whole blood to occlude a collagen-ADP ring, with shorter closure times (CADP-CT) indicating greater reactivity. Impaired microvascular reperfusion was deﬁned as myocardial blush grade 0 or 1 (MBG 0/1) on ﬁnal post-PCI angiogram and the sum of ST-segment resolution <=50% on ECG recorded 30 minutes after PCI relative to the baseline (STR<=50%). An increase of more than 20% in end diastolic volume index (EDVI) at 6-months relative to the baseline value was considered as left ventricular remodeling. Results: Study population was divided according to median CADP-CT (95 seconds). MBG 0/1, STR<=50% and left ventricular remodeling were signiﬁcantly more frequent in the inframedian group (<=95s.) (55.4%, 48.2%, 56% respectively) compared with supramedian group (>95s.) (24.1% and 14.8%, P<0.008, P<0.0002 and P<0.0001, respectively). In multivariate logistic regression model, after adjusting for baseline characteristics CADP-CT <=95s. remained an independent predictor of MBG 0/1 (odds ratio [OR] 5.3, 95% conﬁdence interval [CI] 2.1-13.5, P=0.0004), STR<=50% (OR 8.9, 95% CI 2.9-27.3, P=0.0001) and remodeling (OR 7.6, 95% CI 2.2-27, P=0.0016). The performance of multivariate models after incorporation of CADP-CT showed improvement with the concordance (C) index increase from 0.76 to 0.78 for MBG 0/1, 0.78 to 0.84 for STR<=50% and 0.83 to 0.9 for remodeling. Conclusions: Enhanced platelet reactivity estimated by rapid, point-of-care platelet function analyzer (PFA-100) is a strong and early predictor of impaired microvascular reperfusion and left ventricular remodeling in STEMI treated with primary PCI. 908-169 Inconsistency in the Prevalence of Platelet Aspirin Resistance as Measured by COX-1 Non-Speciﬁc Assays in Patients Treated With 81, 162 and 325 mg Aspirin Udaya Tantry, Kevin P. Bliden, Paul A. Gurbel, Joseph DiChiara, Sinai Center for Thrombosis Research, Baltimore, MD Background: Various estimates of aspirin resistance are reported based on COX-1 non- speciﬁc laboratory measurements. There are no data available regarding comparative measurement of aspirin resistance using different methods simultaneously with different doses of aspirin. Methods: In the present prospective, randomized, double-blinded, double crossover, single-center study, we are evaluating the effect of various doses (81,162 and 325mg) of aspirin in 56 patients with stable coronary artery disease. Patients were randomized to 81mg, 162mg and 325 mg/day for 4 weeks. Blood samples for the measurement of aspirin responsiveness by arachidonic acid-, ADP- and collagen- induced aggregation by light transmittance aggregometry (LTA), VerifyNow and PFA-100 (collagen-epinephrine) were collected at the end of each treatment period. Aspirin resistance was deﬁned as >20% aggregation in LTA, >550 ARU for VerifyNow and <193 seconds for PFA-100. Results: With PFA-100, 40%, 14% and 34% of patients treated with 81mg, 162 mg and 325 mg aspirin respectively exhibited aspirin resistance. With VerifyNow 8%, 6% and 6% of patients treated with 81mg, 162 mg and 325 mg aspirin respectively exhibited aspirin resistance. There was no consistency in the presence of aspirin resistance at different doses or between the methods except for collagen-induced LTA where a dose-dependent response was observed. Conclusions: There is no consistency in the measurement of aspirin resistance between point-of-service assays in stable cardiovascular patients receiving different doses of aspirin. Clinicians should be careful in interpreting the prevalence of aspirin “resistance” indicated by these point-of-care methods. 908-170 Aspirin Resistance Is Strongly Associated With Increased Platelet Turnover Sasidhar Guthikonda, Eli I. Lev, Rajnikant Patel, Timothy DeLao, Angela Bergeron, Jing- Fei Dong, Neal S. Kleiman, Baylor College of Medicine, Houston, TX, The Methodist DeBakey Heart Center, Houston, TX Background: Lack of a platelet inhibitory response to aspirin (ASA) has been termed ‘aspirin resistance’. Immature (reticulated) platelets are a measure of platelet turnover and express both COX-1 (ASA-sensitive) and COX-2 (ASA-insensitive) isoforms, while mature platelets express only COX-1. We tested the hypothesis that increased platelet turnover is associated with a decreased response to ASA. Methods: Sixty healthy subjects (mean age=32±5 years) were recruited. Reticulated platelets (RP) were measured with whole blood ﬂow cytometry using thiazole orange staining. Turbidimetric aggregometry (ADP 5µM, arachidonic acid (AA) 1.5mM, and collagen 1.0µg/ml) was measured at baseline and 24 h after a single 325 mg dose of ASA. ASA resistance was deﬁned as aggregation to ADP 5µM ≥ 70%. Subjects were divided into tertiles based on the % of reticulated platelets. Results: ASA resistance was present in 9/20 subjects (45%) in the upper tertile (mean RP 12%), 2/20 (10%) in the middle tertile (mean RP 8%), and 1/20 (5%) in the lower tertile (mean RP 4%)(P=0.0025). Compared with subjects in the lower tertile, subjects in the upper tertile had higher baseline aggregation to collagen (Table). After ASA, platelet aggregation to ADP and collagen was signiﬁcantly higher in subjects from the upper tertile. Conclusions: Elevated platelet turnover as assessed by platelet reticulation is associated with decreased platelet responses to aspirin, and signiﬁcantly increased aspirin resistance. Table: Baseline platelet aggregation (%) Post-aspirin platelet aggregation (%) Upper tertile RP Lower tertile RP P-value Upper tertile RP Lower tertile RP P-value ADP 5 µM 83 ± 14 72 ± 20 0.06 67 ± 9 53 ± 11 0.0001 AA 1.5 mM 72 ± 28 67 ± 29 0.57 8 ± 7 5 ± 4 0.08 Collagen 1.0 µg/ml 80 ± 7 69 ± 21 0.034 24 ± 8 7 ± 4 <0.0001 908-171 Increased Platelet Sensitivity and Cyclooxygenase-2 Expression in Aspirin Resistance Sasidhar Guthikonda, Eli I. Lev, Rajnikant Patel, Timothy DeLao, Angela Bergeron, Jing- Fei Dong, Neal S. Kleiman, Baylor College of Medicine, Houston, TX, The Methodist DeBakey Heart Center, Houston, TX Background: Aspirin (ASA) resistance is a phenomenon of uncertain etiology describing decreased platelet inhibitory effects of ASA. Cyclooxygenase-2 (COX-2) is expressed in young platelets and may play a role in ASA-independent thromboxane synthesis. Platelets in ASA resistant patients may also be more reactive at baseline. We tested the hypothesis that ASA resistance is associated with increased platelet COX-2 expression and increased platelet reactivity. Methods: Sixty healthy subjects (mean age=32±5 years) were recruited. Baseline platelet sensitivity was tested using low concentrations of ADP, arachidonate (AA) and collagen, with platelet aggregometry (ADP 2µM, AA 0.75mM, collagen 0.375µg/ml), surface p- selectin (AA 0.75mM) and PAC-1 (ADP 2µM). ASA resistance was deﬁned as ADP 5µM- induced aggregation ≥70%, 24 h after 325 mg aspirin dosage. Platelet COX-2 expression was measured with ﬂow cytometry using a FITC-COX-2 antibody. Results: Twelve subjects were ASA resistant. At baseline, ASA resistant subjects showed greater platelet aggregation to ADP and collagen, and higher p-selectin and PAC-1 expression compared with ASA sensitive subjects (Table). Platelet COX-2 expression was signiﬁcantly higher in ASA resistant subjects (15±5.7 vs. 7.5±4.5, P=0.002). Conclusions: Platelets in aspirin resistant subjects have increased basal sensitivity to ADP and collagen. They also exhibit increased COX-2 expression, the functional signiﬁcance of which needs to be studied further. Table: Aspirin Resistant (n=12) Aspirin Sensitive (n=48) P-value ADP 2 µM Aggregation % 62 ± 30 44 ± 25 0.03 Collagen 0.375 µg/ml Aggregation % 73 ± 12 50 ± 30 0.01 AA 0.75 mM Aggregation % 57 ± 42 42 ± 43 0.13 P-selectin with AA 0.75 mM 6.5±2.3 4.7±2.8 0.02 PAC-1 with ADP 2 µM 8.2±1.9 6.8±2.3 0.02 908-172 Anti-Thrombotic Properties of A Novel Nitric Oxide Donor (LA-419) in a Human Model of Thrombosis Mohammad Urooj Zafar, Gemma Vilahur, Brian Choi, Eduardo Salas, Valentin Fuster, Juan Badimon, Mount Sinai School of Medicine, New York, NY Background: Healthy endothlium exerts its protective antithrombotic effect via nitric oxide [NO] synthesis. NO is one of the most potent anti-platelet agents. Nitrates are known to have anti-platelet effect but only at supra-therapeutic doses. A NO donor exerting its effect primarily on platelets could offer the beneﬁt of anti-platelet properties without prohibitive vasodilation. We studied the antithrombotic effect of a novel NO donor LA-419, with known anti-ischemic properties but no vasoactive effects. Methods: Healthy males (n=8) received aspirin (325mg/day) for 3 days prior to participating in 3 consecutive study arms; (a) LA-419 (10mcg/ml), (b) LA-419 (20mcg/ml) and (c) abciximab (4mcg/ml), serving as positive control. Non-anticoagulated blood was perfused through the Badimon chamber for anti-thrombotic assessments pre- and post- treatment, at venous and arterial ﬂow rates. Results: There was a dose-dependent decrease in thrombus formation at both venous and arterial ﬂow conditions with LA-419. Abciximab was a very potent inhibitor of thrombus growth, as expected. ACC_2006_8_VascularDisease.indd 290 1/4/06 5:20:49 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 291A Vascular D isease, H ypertension, and P revention Conclusions: LA-419, a novel NO-donor, shows a dose-dependent antithrombotic effect, evidenced by a signiﬁcant reduction in thrombus formation from baseline values, at both venous and arterial ﬂow conditions. Our observations suggest that the availability of a NO-donor could prove beneﬁcial in the prevention of thrombotic complications of cardiovascular disease and requires further clinical studies. POSTER SESSION 909 Angiogenesis and Repair of Vascular Injury Sunday, March 12, 2006, 9:00 a.m.-12:30 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 909-173 Augmented Vascular Regeneration by Transplanted Human Stem Cell-Derived Vascular Progenitor Cells with Adrenomedullin Ting-Hsing Chao, Hiroshi Itoh, Kenichi Yamahara, Masakatsu Sone, Kazutoshi Miyashita, Kwijun Park, Naofumi Oyamada, Naoya Sawada, Daisuke Taura, Hirokazu Tsujimoto, Akane Nonoguchi, Kazuwa Nakao, National Cheng Kung University Medical Center, Tainan, Taiwan,ROC, Kyoto University Graduate School of Medicine, Kyoto, Japan Background: We have demonstrated that adrenomedullin (AM) could potentiate vascular regeneration. We previously isolated vascular progenitor cells (VPC), which can differentiate into endothelial cells and mural cells, from embryonic stem (ES) cells. We assessed the hypothesis that AM can enhance angiogenesis by transplanted human VPC. Methods: 12-weeks-old of AM-Tg mice, which overproduce AM, were immunosuppressed by cyclosporine A. VEGF-R2+TRA1-VE-cadherin- cells deﬁned as VPC were sorted at day 8 of differentiation. To obtain vascular cells differentiated from VPC (VPC-VC), VEGF- R2+TRA1-VE-cadherin- cells were recultured with VEGF for 3 passages. VPC and VPC- VC were injected intra-arterially into right femoral artery before ligation. To investigate the stimulating effect of AM on endothelial differentiation, we sorted VPC and recultured with VEGF and AM. Results: On day 22, accelerated ﬂow improvement was observed in AM-Tg (n=13) vs. Wt (n=14) (0.77±0.09 vs. 0.53±0.08, p=0.048). There was more ﬂow recovery in VPC- VC+Wt (n=10) (0.98±0.22, p=0.03) and VPC-VC+AM-Tg (n=16) (0.99±0.1, p=0.001) as compared to Wt but not AM-Tg. VPC+AM-Tg mice (n=12) also had marked ﬂow improvement (1.1±0.05) which was signiﬁcantly different from Wt (p=0.001) as well as AM- Tg (p=0.04) despite no signiﬁcant improvement in VPC+Wt (n=11). Immunoﬂuorescence staining showed that endogeneous angiogenesis (mouse PECAM1+) was more in all 3 AM-Tg groups than Wt groups. Cell transplantation itself did not enhance endogeneous angiogenesis. More human PECAM1+ cells appeared, incorporated into host circulating vessel, and formed neovascularization in VPC+AM-Tg than VPC+Wt. Differences of total capillary densities (mouse and/or human PECAM1+) among groups were corresponding to those of LDPI results. On day 8 of incubation, PECAM1+ cells derived from VPC in AM+VEGF groups were more than VEGF only and negative control. Conclusions: AM can enhance endogeneous angiogenesis and transplantation of speciﬁc human ES cell-derived progenitor cells can recruit in vasculogenesis. AM can potentiate the angiogenetic effect of transplanted human VPC, partly mediated by enhancing endothelial differentiation. 909-174 Role of Platelets in Homing of Endothelial Progenitor Cells to the Site of Vascular Injury Eli I. Lev, Neal S. Kleiman, Zeev Estrov, Juan Granada, Khatira Aboulfatova, David Harris, Jing-fei Dong, The Methodist Hospital, Houston, TX, Baylor College of Medicine, Houston, TX Background: Endothelial Progenitor Cells (EPCs) are undifferentiated bone marrow cells that are rapidly mobilized upon vascular or tissue injury. The circulating EPCs home to and differentiate at the site of vessel injury to enhance repair of damaged endothelium. Little is know about how EPCs home to the site where endothelial cells were denuded following injury. We hypothesized that platelets mediate EPC homing because they are the ﬁrst cells that tether and adhere to subendothelium exposed by vascular injury. Accordingly, our aim was to examine whether platelets interact with EPCs under static and ﬂow conditions. Methods: Human EPCs were puriﬁed from buffy coats by cell sorting using CD133 and VEGFR-2 as the cell markers. The EPCs were then incubated with washed platelets that were either at resting state or activated by 5 µg/ml of collagen. EPC-platelet interaction was measured in the form of heterotypic aggregation between two types of cells by ﬂow cytometry (dual labeled with FITC-CD42a and PE-CD133) and by perfusion over a monolayer of activated platelets under a shear stress of 2.5 dyn/cm2 Results: Under static conditions most EPCs attached to platelets. The percentage of platelets binding to EPCs signiﬁcantly increased when platelets were activated by collagen (1.03% vs. 2.75%, p<0.05). The EPC-platelet aggregation was similarly detected in whole blood, washed platelets and platelet-rich plasma. When perfused over a monolayer of activated platelets under shear stress the CD133 positive EPCs tethered to the platelet monolayer. The tethered EPCs either adhered immediately or rolled a short distance before becoming adherent. This EPC-platelet interaction was calcium-dependent and inhibited by up to 60±11.5% by a polyclonal P-selectin antibody. In comparison eptiﬁbatide and the monoclonal GP Ibα antibody AK2 (which blocks GP Ib-VWF interaction) had no inhibitory effect. Conclusions: These results demonstrate for the ﬁrst time a signiﬁcant interaction between platelets and EPCs and suggest that platelets may function as carrier cells that direct EPCs to the site of vascular injury. In addition to homing, platelets may provide a supporting matrix on which adherent EPCs differentiate. 909-175 Sildenaﬁl Enhances Angiogenesis After Mice Hindlimb Ischemia Ray D. Smith, Annamalai Senthilkumar, Jayant Khitha, Will Langston, John H. Chidlow, Jr., Shayne C. Barlow, David J. Lefer, Xinjun Teng, Rakesh P. Patel, Christopher G. Kevil, Louisiana State University Health Sciences Center, Shreveport, LA, University of Alabama at Birmingham, Birmingham, AL Background: Nitric oxide (NO) enhances angiogenesis via a cyclic guanosine monophosphate (cGMP) pathway. We tested the hypothesis That Sildenaﬁl, a phosphodiesterase type 5 inhibitor would augment tissue cGMP levels and enhance angiogenesis in the setting of hind limb ischemia. Methods: Hind limb ischemia was induced in mice by ligating the left common femoral artery. Mice (4 groups With n=5/group) were treated With Sildenaﬁl (0.1 mg/kg/day) or vehicle in drinking water. At 7 and 21 days After ligation, gastrocnemius muscle sections were stained With anti-PECAM-1 and DAPI for the endothelium and nuclei respectively. The ratio of PECAM-1 to DAPI staining was used as an angiogenic index (AI) to measure vascular density. Tissue cGMP and nitrite levels were also measured at day 21. Results: The AI was increased in Sildenaﬁl ischemic limbs Versus vehicle control ischemic limbs at 7 days (0.630 ± 0.104 Versus 0.304 ± 0.024, p <0.01) and 21 days (0.875 ± 0.087 Versus 0.495± 0.046, p < 0.001). At day 21, nitrite levels (µM/mg tissue) were signiﬁcantly increased in vehicle control ischemic limbs (0.02663 ± 0.01344) but Not in Sildenaﬁl ischemic limbs (0.008174 ± 0.00236). Tissue cGMP levels (pg/mL/mg tissue) were signiﬁcantly elevated in Sildenaﬁl ischemic limbs (0.0390 ± 0.0035) compared to vehicle control ischemic limbs (0.0163 ± 0.0021, p <0.001). Conclusions: Sildenaﬁl enhances angiogenesis in response to hind limb ischemia That Is mediated by increased cGMP and independent of NO. 909-176 Phosphoinositide 3-kinase γ Modulates Vascular Endothelial Growth Factor Release and Collateral Vessel Development Following Hindlimb Ischemia Giovanni Esposito, Cinzia Perrino, Antonio Rapacciuolo, Eugenio Stabile, Francesco Borgia, Enza Capasso, Annalisa De Concilio, Annalisa Scognamiglio, Massimo Chiariello, University Federico II, Naples, Italy Background: Phosphoinositide 3-kinase γ (PI3Kγ) belongs to a conserved family of protein kinases regulating important cellular functions such as cell survival and proliferation. ACC_2006_8_VascularDisease.indd 291 1/4/06 5:20:50 PM 292A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n Although vascular endothelial growth factor (VEGF) receptor signaling has been linked to PI3Ks, the role of PI3Kγ in the angiogenic process has been poorly studied. Methods: To test the hypothesis that PI3Kγ activation is beneﬁcial in response to hindlimb ischemia, we surgically ligated the femoral artery in wild-type mice (129/BL6, WT) and PI3Kγ knockout mice (PI3Kγ-/-). Results: After 21 days, laser doppler perfusion imaging studies showed a signiﬁcantly reduced blood ﬂow recovery in PI3Kγ-/- mice compared to WT (Figure). In addition, PI3Kγ-/- mice displayed signiﬁcantly greater interstitial ﬁbrosis and calf muscle atrophy. 48 hours of hindlimb ischemia rapidly induced in WT mice a signiﬁcant increase in VEGF levels (2.8 ± 0.4 fold induction by ischemia, p<0.001) and extracellular signals regulated protein kinase (ERK) activation (2.5 ± 0.8 fold induction, p<0.01). Interestingly, these responses were abolished in PI3Kγ-/- mice (for VEGF, 1.2 ± 0.3 fold induction, p=NS; for ERK, 1.2 ± 0.6 fold induction, p=NS). Conclusions: PI3Kγ activation plays a protective role in response to hindlimb ischemia, regulating VEGF release and arteriogenic growth. These results demonstrate a novel molecular mechanism to modulate angiogenesis in response to peripheral ischemia. 909-177 A New Strategy for Atherosclerosis Using Sendai Virus Mediated Delivery of Paraoxonase Miwa Miyoshi, Yukiko Nakano, Takemasa Sakaguchi, Hiroshi Ogi, Noboru Oda, Katuhiro Kiyotani, Masao Yoshizumi, Tetsuya Yoshida, Kazuaki Chayama, Hiroshima University, Hiroshima, Japan Background Paraoxonase-1(PON-1), an enzyme associated with high-density lipoproteins (HDLs) ,has a protective effect against oxidative damage to the circulating cells and lipoproteins, which results in an anti-atherosclerosis effect. The PON-1 knockout mice or a variety of avian species which naturally lack PON-1 are unable to prevent the lipid peroxidation of LDLs, because PON-1 has antioxidant properties. This study evaluated the effects of the gene transfection of PON-1 on the balloon injured iliac arteries of high fat diet rabbits. Methods and Results We injured the iliac arteries in 11 high fat diet rabbits and performed local gene transformation using a Sendai virus vector containing the PON-1 gene (n=7) or EGFP gene (n=4). After 7-10 days, the animals were analyzed. The total cholesterol and LDL levels in the PON-1 administrated group were higher than those in the EGFP group. The HDL and CM levels were similar in both groups. The PON-1 gene transfer greater reduced the lesion intima/media ratios and positive Oil red O stained areas than did the EGFP gene. Immunohistochemistry revealed that RAM11, VEGF and HNE(4-hydroxynoneanal)positive area were reduced in the PON-1 administrated group. MMP3 protein level of Western blotting in the PON-1 administrated group were reduced Oppositely,HO-1 level was elevated than the EGFP group. Conclusions We concluded that the PON-1 gene transfection was effective in preventing atherosclerosis and preserving the normal construction of vessels. Key Words: arteriosclerosis, viruses, immunohistochemistry , hypercholesterolemia,remodeling 909-178 Synchrotron Radiation Coronary Microangiography for Morphometric and Physiological Evaluation of Myocardial Neovascularization Induced by Cell-Based Transplantation Hiroto Iwasaki, Atsuhiko Kawamoto, Kazuhito Fukushima, Keiji Umetani, Akira Oyamada, Saeko Hayashi, Kayoko Gokurakuji, Tomoyuki Matsumoto, Toshihiko Shibata, Shigefumi Suehiro, Takayuki Asahara, Kobe Institute of Biomedical Research and Innovation / RIKEN Center for Developmental Biology, Kobe, Japan, Osaka City University Graduate School of Medicine, Osaka, Japan Background: Recently, therapeutic neovascularization by stem cell transplantation (SCTx) has been clinically applied. However, it has been sometimes difﬁcult to obtain evidence of collateral formation by SCTx with conventional angiography system. We utilized novel sychrotron radiation microangiograhy (SRM) with a spatial resolution of 20 µm to visualize collateral microvessels and evaluate physiological function of the neovasculature following SCTx. Methods: Peripheral blood CD34+ cells, which are endothelial progenitor-enriched cell population and have therapeutic potential of myocardial neovascularization, were isolated from total mononuclear cells of a patient with critical limb ischemia. PBS, 1x105 CD34- cells, or 1x105 CD34+ cells were intramyocardially transplanted after ligating LAD of nude rats. Coronary microangiography of ex vivo beating hearts 28 days after SCTx under the Langendorf perfusion technique was performed utilizing the third generation SRM with a new rotating disk shatter for high-resolution and real-time imaging. Results: Rentrop score of collateral development was signiﬁcantly greater in CD34+ cell group than other groups (CD34+, 1.5±0.1; CD34-, 0.56±0.16; PBS, 0.35±0.17, P<0.01 for CD34+ vs CD34- and PBS). To assess the physiological function of neovasculature, angiographical microvessel density (AMVD) in the occluded LAD area pre and post infusion of sodium nitroprusside (SN) was evaluated by computed analysis. Ratio of AMVD post SN with that pre SN was signiﬁcantly augmented in CD34+ cell group than in other groups (CD34+, 2.47±0.49; CD34-, 1.15±0.11; PBS, 1.1±0.06, P<0.05 for CD34+ vs CD34- and PBS), whereas histological capillary density (HCD) at day 28 indicated augmentation of ischemic neovascularization in CD34+ cell group (CD34+, 714.3±25.0; CD34-, 365.8±31.0; PBS, 291.3±19.0 /mm2, P<0.05 for CD34+ vs CD34- and PBS). AMVD post NP was closely correlated with HCD (R= 0.88, P<0.01). Conclusion: The SRM may be useful for morphometric and physiological evaluation of coronary collateral formation by SCTx. The novel imaging system may be an essential tool in future preclinical/ translational research of stem cell biology. POSTER SESSION 910 Percutaneous Coronary Intervention: Atherosclerosis and Restenosis Sunday, March 12, 2006, 9:00 a.m.-12:30 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 910-179 Percutaneous Coronary Intervention Increases Endothelial Progenitor Cell Mobilisation in Patients With Ischemic Heart Disease Nicholas L. Mills, Olga Tura, Chris Millar, Ninian Lang, David Stirling, Christopher A. Ludlam, Marc Turner, Robin G. Barclay, David E. Newby, The University of Edinburgh, Edinburgh, United Kingdom, Scottish Blood Transfusion Service, Edinburgh, United Kingdom Background: Endothelial progenitor cells (EPCs) are circulating mononuclear cells with the capacity to mature into endothelial cells, and to contribute to the process of vascular repair. We assessed the effect of local vascular injury during percutaneous coronary intervention (PCI) on circulating levels of EPCs in patients with stable coronary disease. Methods: Forty patients undergoing elective coronary angiography were studied; 20 underwent diagnostic angiography alone and 20 PCI with balloon angioplasty and stenting. We collected peripheral blood before catheterisation, immediately following the procedure, at 6 hours and at 24 hours. Endothelial progenitor cells were quantiﬁed in whole blood by ﬂow cytometry (CD34+KDR+ cells) and by real-time PCR of leucocyte mRNA sequences (CD34, KDR, CD14), with functional EPCs quantiﬁed using a colony forming unit (EPC CFU) assay. Markers of inﬂammation and myocardial necrosis were assessed before and 24 hours after the procedure. Results: Diagnostic angiography did not cause myocyte necrosis, systemic inﬂammation or affect the number of circulating EPCs. PCI increased the number of circulating neutrophils (1.31±0.35 x109 cells/L, P<0.001) at 24 hours, without signiﬁcant release of Troponin I (0.04±0.01 µg/L, P=NS). The number of EPCs cultured from peripheral blood increased 24 hours following PCI (0.06±0.02 vs. 0.23±0.09 x105 CFU, P=0.05), although there was no increase in leucocyte CD34 mRNA (2.26±0.48 vs. 2.10±0.42 RQ, P=NS), or CD34+KDR+ cells (0.02±0.004 vs. 0.03±0.006 % leucocytes, P=NS). There was no correlation between the number of CD34+KDR+ cells and functional EPC CFUs (r=0.02, P=0.44). Conclusions: Local vascular injury following PCI results in a systemic inﬂammatory response and an increase in the number of functional EPCs. This was not associated with an increase in CD34+KDR+ cells suggesting this cell type is not the primary source of functional endothelial progenitor cells. 910-180 Which Patients Develop New Lesions Post Percutaneous Coronary Intervention? The Impact of Initial Clinical Syndrome and the Smokers ‘Paradox’ Konstantinos Toutouzas, John Mitopoulos, Christos Deboneras, Eleftherios Tsiamis, Costas Tentolouris, Elli Stefanadi, Manolis Vavuranakis, Christodoulos Stefanadis, Hippokration Hospital, Athens, Greece Background: The risk factors for the development of a new symptomatic lesion progression after percutaneous coronary intervention (PCI) are still under investigation. The aim of the present study was to investigate the predictors of development of a new lesion after percutaneous coronary intervention (PCI). Methods: We included patients who had two coronary angiograms with a time interval greater than three months. The ﬁrst angiogram was performed due to either acute coronary syndrome (ACS) or stable angina (SA). The culprit lesion of the ﬁrst angiogram was clearly identiﬁed by a combination of ECG, wall motion abnormalities, scintigraphic perfusion defects, and coronary angiogram. All pts underwent PCI for the treatment of the culprit lesion. In the second angiogram we investigated whether they had a new culprit lesion clearly differentiated from the culprit lesion of the ﬁrst angiogram. In all patients we recorded demographic, clinical, angiographic and procedural characteristics. Results: We included 179 pts (mean age 63.2±10.8 years) with 2 angiograms during a follow-up period of 11.3±5.7 months. The majority of the study population was treated due to ACS (112 pts, 63%), while the rest had SA (67 pts, 37%). The primary endpoint was met in 48 pts (26%). The development of a new lesion was proven angiographically in all pts. We performed multivariate regression analysis including variables in which in the univariate analysis p value was <0.15. Patients presenting with ACS had 3 times greater risk for developing new lesion after PCI (coefﬁcient= 3.01, p=0.003). Indeed, 43% of pts with ACS had a new lesion during the follow-up versus 18% of pts with SA (p < 0.01). However, current smoking was associated with lower risk (coefﬁcient= 0.3, p=0.01). Conclusions: Patients presenting with ACS had a greater risk of developing a new ACC_2006_8_VascularDisease.indd 292 1/4/06 5:20:51 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 293A Vascular D isease, H ypertension, and P revention signiﬁcant lesion after PCI. Interestingly, current smokers seem to have lower risk of developing such lesions. 910-181 Early and Subtle Neointimal Growth Detection Following Stent Implantation Using Optical Coherence Tomography and Intravascular Ultrasound and Histology Toru Kataoka, Yoshiki Kobayashi, Koichiro Asawa, Hideshi Ishii, Nobuyuki Shirai, Ryo Matsumoto, Takao Hasegawa, Hiroki Nishioka, Hajime Yamashita, Shoichi Ehara, Makoto Hirose, Kimio Kamimori, Kenei Shimada, Minoru Yoshiyama, Junichi Yoshikawa, Osaka City University Medical School, Osaka, Japan, Osaka Ekisaikai Hospital, Osaka, Japan Background: In this drug-eluting stent era, the importance of neointimal formation following stent implantation has become critical issue. However, the mechanisms of neointimal growth within the stent are still unclear. Thus, the aim of this study is to investigate the detailed mechanisms of neointimal growth using optical coherence tomography (OCT), intravascular ultrasound (IVUS), and histology. Methods: Five miniature pigs were used. At peripheral arteries, stent implantation was performed. OCT and IVUS were performed immediately after stent implantation and at 1 and 4 weeks follow-up stage, using a motorized pullback device at 1mm/sec. Identical 87 cross sections from 7 stented segments between OCT and IVUS, conﬁrmed by landmarks, were examined. Neointimal area was deﬁned as stent area minus lumen area. For the detailed analysis, stent strut coverage with neointima was classiﬁed into 3 categories: 0; uncovered, 1; partially covered, and 2; completely covered. Neointima thickness on the stent strut was measured. At selected segments, histological analysis was also performed. Results: At 1 and 4 weeks follow-up, OCT detected greater neointima cross section compared to IVUS (1week: OCT 93%, vs. IVUS 5%, p<0.0001, 4weeks: OCT 100%, vs. IVUS 31%, p<0.0001). OCT analysis showed an increase in stent coverage score (1week; 0.84±0.55 vs. 4week: 1.71±0.26, p<0.0001) as well as neointima thickness on the stent (1week: 0.023±0.024mm vs. 4week: 0.071±0.053mm, p<0.0001). Histological analysis revealed comparable neointimal growth detection to OCT (neointima coverage; 1week: 100%, 4weeks: 100%, stent coverage score; 1week: 0.64±0.22, 4week: 1.93±0.20, neointima thickness; 1week: 0.009±0.005mm, 4week: 0.145±0.115mm) Conclusion: Similar to histology, OCT could detect the early and subtle neointimal growth more precisely compared to IVUS. These results suggest OCT may contribute to a more detailed investigation of the vascular response after stent implantation, in addition to safety evaluations for studies involving drug-eluting stents. 910-182 Neointimal Hyperplasia But Not Pathological Vascular Wall Structural Changes (Fibrin Deposition and Inﬂammation) Inﬂuence Maximal Vasodilation in Porcine Coronary Arteries 1-Month After Implantation of Stents Serdar Farhan, Johannes Matiasek, Christoph Strehblow, Noemi Pavo, Wofgang Sperker, Aliasghar Khorsand, Dietmar Glogar, Kurt Huber, Mariann Gyongyosi, Medical University of Vienna, Vienna, Austria, University of Kaposvar, Kaposvar, Hungary Background. The aim of our study was to investigate the inﬂuence of the histopathological changes of the arterial wall (ﬁbrin deposition, local inﬂammation, media necrosis and haemorrhagia) on the maximal vasodilatation capacity in porcine coronary arteries 1 month after stent implantations Methods. Bare metal (BMS) (n=40) or paclitaxel drug-eluting stents (DES) (n=31) were implanted in the LAD and LCx coronary arteries under general anaesthesia. After 4-week, during diagnostic coronary angiography, pressure wire (PW) measurements (wire placed distal to the stent) using intracoronary adenosine (40 ug) were performed. Histopathologic (ﬁbrin deposition, intina, media and adventitia inﬂammation, media necrosis, haemorrhagia and injury score) and histomorphometric (lumen, neointimal, internal elastic lamina, IEL, media, external elastic lamina, EEL, and adventitia areas, the remodeling index and proximal and distal edge effects) parameters of the explanted arteries were correlated with the FFR after adenosine by using uni- and multivariate regression analysis. Cut- off values of FFR of hemodynamic signiﬁcance of a stent-stenosis in porcine coronary arteries were determined by receiver operator characteristic analysis. Results. Maximal ﬁbrin deposition and adventitial inﬂammation were signiﬁcantly elevated in pigs with DES as compared with BMS, and endothelialization was signiﬁcantly more complete in BMS group. In contrast, signiﬁcantly smaller neointimal area with higher minimal lumen area and less %AS was measured in DES group as compared with the BMS group. For the entire group, ROC analysis revealed a cut-off point of 0.80 for a FFR with a predictive accuracy of 0.86 and speciﬁcity/sensitivity of 79%, with no difference between the cut-off points determined separately in DES and BMS groups. Multivariate analysis resulted in neointimal area as a single signiﬁcant independent predictor (p<0.001) for hemodynamic dysfunction of the stented artery fo FFR. Conclusions. Implantation of a DES impairs wall structure as compared with BMS, but to a certain degree and time, it does not lead to impaired vasodilatory response to maximal hyperaemic stimuli. 910-183 Yellow Color Plaques Were Still Observed Among the Sirolimus Eluting Stent Struts at 3 and 6-Month Follow- Up Via Coronary Angioscope Takafumi Ueno, Masatomo Ikeguchi, Yoshihisa Fujiura, Junichiro Shimamatsu, Yasuki Nanjou, Fukuoka City Medical Association Hospital, Fukuoka, Japan Background:The effectiveness of the sirolimus-eluting stent (SES) against restenosis has been shown in many clinical trials. Recent reports have raised concern for the potential for late stent thromboses related to delayed reendothelialization of the stent struts. However, the character of neointima of SES at follow-up has not yet been clear in human. Our hypothesis is that if stent thrombosis in SES is related to delayed reendothelialization, this should be observable with coronary angioscopic evaluation. Methods: Neointimal coverage in patients with SES implantation was evaluated by coronary angioscopy retrospectively. Thirty patients with stable angina were included in this study. 12 patients were implanted with both SES and BMS simultaneously (SES; n=16 lesions, BMS; n=12 lesions). 18 patients were implanted with SES alone (SES; n=24 lesions). Follow-up angioscopy was performed at 3 months (SES; n=10, BMS; n=6) and 6 months (SES; n=20, BMS; n=6). Semiquantitative evaluation of neointimal stent coverage was performed by the neointimal coverage score: 0 = complete exposure of stent struts, 1 = exposure of stent struts with partial coverage, 2 = > 50% coverage, 3 = almost complete coverage with slightly visible stent struts, 4 = complete coverage. Results: Restenosis was observed in one case of BMS, but not in SES and treated lesions at 3 or 6 month follow-up. At 3 month follow-up, all stent struts were clearly visible in SES implanted lesions, while all struts were covered with white neointima in BMS implanted lesions. Neointimal coverage score of SES is signiﬁcantly lower than BMS (3.4 vs 1.5). At 6 month follow-up, most stent struts of SES were covered by the neointima or ﬁbrin, but were still visible through the over-layered material and some struts of SES were still clearly observed. Neointimal coverage score of SES is still signiﬁcantly lower than BMS (3.5 vs 1.9). Moreover, yellow color plaques were observed in 70% of SES implanted cases. Conclusions:Coronary angioscopy revealed that the SES remarkably inhibits neointimal proliferation, compared to BMS at 3 and 6 month follow-up. However, one of the mechanisms of late thrombosis might be the rupture of plaque among the SES struts. 910-184 Comparative Pathologic Studies of Vascular Tissue Responses to Sirolimus-Eluting and Bare Metal Stent Implantation in Human Coronary Arteries Katsumi Inoue, Yukinobu Nakamura, Nobuo Shiode, Norihiko Morita, Kazuaki Mitsudo, Masakiyo Nobuyoshi, Matsue Red Cross Hospital, Matsue, Japan, Matsunami General Hospital, Gifu, Japan, Kokura Memorial Hospital, Kitakyushu, Japan, Kurashiki Central Hospital, Kurashiki, Japan Background: Despite the increasing use of sirolimus-eluting stents (SES), few reports have described human coronary artery pathology after SES implantation. Methods and Results:To evaluate and compare the temporal mode of vascular responses after SES (1.5 to 4 months(M), 5 lesions) and bare metal stent (BMS; 2 days(D) to 4 M, 19 lesions) implantation, necropsied coronary arteries were investigated macroscopically, histologically and immunohistochemically. In arteries that had been implanted with SES for 1.5 M, the stent struts were focally (<5%) covered by thin membranous tissue mainly composed of ﬁbrin deposition.Furthermore, only minimal cellular reactions by smooth muscle cells (SMCs) and endothelial cells (ECs) were observed around the struts. These ﬁndings were nearly equal to those of BMS specimens at 7 to 10 D. In contrast, complete coverage of BMS by neointimal tissue composed of SMCs and extracellular matrix (ECM) was documented at 1 M. Furthermore, >75% of the BMS surface was reendothelialized. The luminal surface of SES after 2.5 M was scarcely (10 to 15%) covered by very thin neointimal tissue. Few SMCs were observed in this portion, but abundant ﬁbrin deposits were present around the struts. There was an intense inﬂammatory reaction involving T lymphocytes (T cells), macrophages (Mφ) and multinucleated giant cells adjacent to the SES struts. A localized granulomatous reaction was also visible around the struts, but apparent inﬁltration of B cells or eosinophils were not recognizable. Even at 4 M, >80% of the SES segment was not covered by neointima. Remarkable intimal ﬁbrin deposition and inﬂammation surrounding the stent struts were still present. In BMS segments at 4 M, signiﬁcant proliferation of pleomorphic SMCs and an increase in ECM were observed on the intimal side of the stent struts. Although there were occasional T cells, M�, and giant cells around the BMS struts, the extent of inﬂammation was far less than for SES. A small amount of ﬁbrin deposits was observed only occasionally in close contact with these struts. Conclusions: These ﬁndings suggest that careful long-term follow-up of patients with SES is needed to prevent late in-stent restenosis and thrombosis. 910-185 Relationship of Shear Stress With In-Stent Restenosis: Bare Metal Stenting Versus Bare Metal Stenting and Adjunctive Brachytherapy Michail I. Papafaklis, Christos V. Bourantas, Panagiotis E. Theodorakis, Christos S. Katsouras, Dimitrios I. Fotiadis, Lampros K. Michalis, Michaelideion Cardiac Center, University of Ioannina, Ioannina, Greece, Medical School, University of Ioannina, Ioannina, Greece Background: The association of endothelial shear stress (ESS) with in-stent restenosis after coronary artery stenting is not clear. We investigated the signiﬁcance of ESS on predicting areas with neointimal thickness (NTh) and the effect of vascular brachytherapy (VBT) following coronary artery stenting on this relationship. Methods: By using coronary angiography and intravascular ultrasound, we performed 3D artery and stent reconstruction in 12 patients at 8-month follow-up following coronary artery stenting with or without adjunctive beta-VBT (90Strontium/90Yttrium) (6 patients in each group). In-stent endothelial shear stress was calculated by applying computational ﬂuid dynamics to the stent reconstruction and neointimal thickness was determined in 3D space. A linear mixed model controlling for patient-to-patient variation was used for estimating the relationship of ESS with NTh and the effect of VBT on this relationship. Results: Baseline demographic and procedural characteristics were similar in the two groups. Computed NTh volumes in the 3D models did not differ between the two groups (mean NTh volume ± standard error of mean: 29.32±7.75 mm3 vs. 26.11±13.2 mm3 in the bare stent vs. the stent&VBT group respectively, p=0.2). The estimated intercepts and slopes were 0.29mm [95% conﬁdence interval (CI):0.16-0.41mm] and -0.08mm/Pa [95% CI: (-0.084)-(-0.076)mm/Pa] respectively for the bare stent group and 0.22mm (95% CI: 0.09-0.36mm) and -0.1mm/Pa [95% CI: (-0.11)-(-0.092)mm/Pa] respectively for the stent&VBT group and all were signiﬁcant at p level <0.01. When all data were analyzed together, a signiﬁcant effect of VBT on the relationship between NTh and ESS was found [estimate of interaction term (group*ESS) for stent&VBT group vs. stent group: -0.019mm/ ACC_2006_8_VascularDisease.indd 293 1/4/06 5:20:51 PM 294A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n Pa, 95% CI: (-0.026)-(-0.01)mm/Pa, p<0.001]. Conclusions: In-stent restenosis is inversely related to shear stress after coronary artery stenting and vascular brachytherapy augments this inverse relationship. POSTER SESSION 911 Peripheral Arterial Disease Risk Factors Sunday, March 12, 2006, 9:00 a.m.-12:30 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 911-186 Plasma Asymmetric Dimethylarginine is an Independent Marker for the Presence and Severity of Peripheral Artery Disease Martin K. Ng, Themistocles Assimes, Bing Y. Wang, Sarah McGee, Randall K. Harada, Alan C. Yeung, Balasubramanian Narasimhan, Jeffrey W. Olin, John P. Cooke, Stanford University School of Medicine, Stanford, CA, Royal Prince Alfred Hospital, Sydney, Australia Background: Plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase causally linked to endothelial dysfunction, are elevated in those with risk factors for atherosclerosis and may be a novel risk factor for atherosclerosis. We sought to study the relationship between plasma ADMA and the presence and severity of peripheral artery disease (PAD). Methods: As part of a prospective multicenter study, subjects referred for cardiac catheterization (n =280; age, 66±1 years; percentage male patients: 57%) underwent history and physical examination, determination of serum chemistries and ADMA levels, and measurement of ankle brachial indices (ABI). Results: The mean ABI of the cohort was 0.95±0.01 and 28% (n=80) of patients had PAD (as deﬁned by ABI<0.9). ADMA concentrations were elevated in PAD patients (0.63±0.03µmol/L) compared to those without PAD (0.55±0.01µmol/L)(P=0.03 for PAD Vs non-PAD). Univariate and multivariate analyses revealed that plasma levels of ADMA were positively correlated with body mass index (P=0.002), mean arterial pressure (P=0.01) and male gender (P=0.03) but negatively correlated with glomerular ﬁltration rate (P<0.0001). In multivariate analysis plasma ADMA was negatively correlated with ABI (P=0.0003). In a multivariate logistic regression, increasing plasma ADMA was independently associated with the presence of PAD (P=0.02). After adjustment for risk factors, patients in the quartile with the highest ADMA values were 4 times more likely to have PAD than those in the lowest quartile (adjusted OR 4.2 [95%CI 1.4-12.2]; P=0.009). Furthermore, plasma ADMA correlated with functional severity of PAD, being inversely related to: 1) subject walking speed; 2) walking distance and; 3) to stair climbing capacity (P<0.03). Conclusions: Plasma ADMA is signiﬁcantly correlated with the presence and severity of PAD as measured by ABI. Furthermore, plasma ADMA correlates with the functional severity of PAD. Our ﬁndings are consistent with the hypothesis that ADMA may be a novel biomarker for atherosclerosis. 911-187 Novel Risk Factors Are Associated With Ankle Brachial Index in African Americans and Non-Hispanic Whites Farhan J. Khawaja, Stephen T. Turner, Sharon L. Kardia, Thomas Mosely, Jr., Kent R. Bailey, Iftikhar J. Kullo, Mayo Clinic, Rochester, MN Background: We investigated whether novel risk factors - C-reactive protein (CRP), ﬁbrinogen, lipoprotein(a) (Lp(a)), and homocysteine - are related to the ankle brachial index (ABI) independent of conventional risk factors (age, sex, total and HDL cholesterol, body mass index, smoking, hypertension, and diabetes) in African Americans (AA) and non-Hispanic whites (NHW). Methods: Subjects including 1395 AA (mean age 63±9 y, 71% women) and 834 NHW (mean age 58±9 y, 62% women), belonged to hypertensive sibships. ABI was determined at 2 sites in each lower extremity and averaged. The lower of the 2 average ABIs was used in the analyses. Novel risk factors were measured using validated assays. CRP, Lp(a), and homocysteine levels were log transformed to reduce skewness. Multivariable stepwise linear regression analyses (using generalized estimating equations to account for intrafamilial correlations) were used to assess whether the novel risk factors were related to ABI after adjustment for conventional risk factors. Results: Mean ABI was lower in AA than NHW (0.99±0.1 vs. 1.13±0.1, P < 0.0001). Conventional risk factors predicted only 14.7% of variation in ABI in AA and 13.6% of variation in ABI in NHW subjects. In AA subjects, higher levels of CRP (P < 0.0001), ﬁbrinogen (P < 0.0001), Lp(a) (P < 0.0001), and homocysteine (P = 0.031) were independent predictors of a lower ABI. When the 4 novel risk factors were included together in a multivariable regression model, each remained an independent predictor of ABI and the Model R2 increased to 0.181. In NHW subjects, higher CRP (P = 0.008), ﬁbrinogen (P = 0.010), and homocysteine (P = 0.045) levels were each independent predictors of a lower ABI. When the 4 novel risk factors were included together in a multivariable regression model, only CRP remained an independent predictor of ABI and the Model R2 increased to 0.158). Conclusion: Higher levels of CRP, ﬁbrinogen, and homocysteine are independently associated with a lower ABI in both AA and NHW subjects. In AA subjects, Lp(a) is also signiﬁcantly associated with a lower ABI. Novel risk factors explain a greater proportion of variation in ABI in AA than in NHW subjects. 911-188 Self-Reported Peripheral Arterial Disease Predicts Risk of Combined Vascular Events Beyond the Framingham Risk Score in the Northern Manhattan Study Maya Salameh, Tatjana Rundek, Daniel Jacoby, Zhezhen Jin, Elizabeth Ratchford, Bernadette Boden-Albala, Shunichi Homma, Ralph L. Sacco, Columbia University Medical Center, New York, NY Background: Lower extremity peripheral arterial disease (PAD) is strongly associated with cardiovascular morbidity and mortality. We have previously shown that self-reported PAD (srPAD) in a multiethnic population of Northern Manhattan is signiﬁcantly associated with increased risk of combined vascular events (ischemic stroke, myocardial infarction, or vascular death). We sought to determine if the presence of srPAD predicts the risk of combined vascular events beyond the Framingham Heart Risk Score (FRS). Methods: Subjects from the population-based Northern Manhattan Study (NOMAS) prospective cohort with either claudication or a self-reported prior history of PAD were classiﬁed as having srPAD. Claudication was deﬁned as exercise-induced pain in the back of the legs relieved by rest. Subjects were categorized according to FRS into low (<10% 10 year risk), intermediate (10-20%), and high risk groups (>20%). The ﬁve-year risk of combined vascular events in subjects with and without srPAD was compared for each group, and then linearly extrapolated to 10 year risk for comparison to FRS data. Results: Among 3083 participants (mean age 69 yrs; 63.1% women; 52.6% Hispanic; 24.2% African-American; 20.9% Caucasian), the prevalence of srPAD was 15%. After a mean follow- up of 5.5 years, 397 total combined vascular events were detected. The 5 year cumulative risk of combined vascular events for 2610 subjects without srPAD was 4.1%, 8.7%, and 17.1% for low, intermediate, and high risk FRS groups respectively; versus 4.2%, 11.7%, and 29.1% for 473 subjects with srPAD. Extrapolated 10 year risk for subjects without srPAD was 8.2%, 17.4%, and 34.2% for low, intermediate, and high risk groups respectively, consistent with FRS data; versus 8.4%, 23.4%, and 58.2% for subjects with srPAD. Conclusion: The presence of srPAD is predictive of an increased risk of vascular events beyond that expected by FRS alone in both intermediate and high risk groups; and extrapolated 10 year risk for the intermediate group exceeds 20%. Accordingly, adding srPAD to the Framingham Heart Risk Score may help reclassify a proportion of patients from intermediate to high risk, thereby potentially inﬂuencing their treatment. 911-189 Limitation of Ankle-Brachial Blood Pressure Index for Diagnosis of Peripheral Vascular Disease in Young and Middle Age Adults: The Bogalusa Heart Study Timir Paul, Sathanur Srinivasan, Sharon Jackson, Paolo Raggi, Wei Chen, Gerald Berenson, Tulane University, New Orleans, LA, East Tennessee State University, Johnson City, TN Background: Ankle brachial blood pressure index (ABI) is a noninvasive indicator of peripheral arterial diseases (PAD) in older individuals; but, information in this regard in young adults is limited. This study examined the limitation of ABI for diagnosis of PAD in asymptomatic young and middle age adults. Methods: ABI was measured by dividing ankle-systolic blood pressure by brachial- systolic blood pressure obtained from Collin machine in 867 subjects (aged 24-44 years; 72% white, 44% male) enrolled in the Bogalusa Heart Study. Individuals in the bottom (ABI ≤ 0.99; n= 44) vs top 5th (ABI ≥ 1.27; n=50) percentiles distribution of ABI were compared for traditional cardiovascular risk factors proﬁle. Results: There were only 6 (0.7%) individuals having clinically cut point ABI of ≤ 0.9. Females especially black females had lower ABI than males (p<0.0001). Blacks had lower ABI compared to whites (p<0.0001). The bottom vs top 5th percentiles of ABI did not differ signiﬁcantly with respect to age, body mass index (BMI), waist circumference, systolic and diastolic blood pressure, total cholesterol, LDL cholesterol, non-HDL cholesterol, HDL cholesterol, triglycerides, glucose, insulin, cigarette smoking status and femoral and carotid intima-media thickness (IMT). In terms of prevalence of clinically deﬁned traditional risk factors, individuals at the bottom vs top 5th percentile of ABI distribution had not had signiﬁcantly higher prevalence of high LDL cholesterol, non-HDL cholesterol, triglycerides, low HDL cholesterol, high blood sugar and high blood pressure. Further, these subjects had not had signiﬁcantly higher prevalence of high BMI, waist circumference, femoral IMT, abnormal ECG, and higher smoking status. Subjects with ABI less than 0.99 did not display signiﬁcantly higher prevalence of multiple risk factors compared to ABI ≥ 1.27. Conclusions: The prevalence of abnormal ABI in this population is extremely low because of the relatively younger study population. The lack of association of traditionally cardiovascular risk factors with the lower ABI indicates that using ABI as a screening tool for diagnosis of PAD is not useful and cost-effective in younger and middle aged adults. 911-190 Combination of Mild Renal Insufﬁciency and Peripheral Artery Disease Accelerate Long-Term Events Risk in Patients With Chest Pain Hideki Itaya, Masato Nakamura, Masanori Shiba, Hisao Hara, Rintaro Nakajima, Toho University Ohashi Medical Center, Tokyo, Japan Background: Both the presence of peripheral arterial disease and mild renal insufﬁciency has been reported to be independent risk factors associating with poor prognosis. Methods: We analyzed long-term outcome in consecutive 715 patients underwent coronary angiogram for the evaluation of chest pain. Patients on hemodialysis were excluded from this analysis. Cohort patients were divided into 4groups according to the Ankle Brachial Index (ABI<0.9) and the value of creatinine clearance (Ccr<50ml/ min). GroupA (n=498; ABI>0.9, Ccr>50), B(n=65, ABI<0.9, Ccr>50),C (n=99; ABI>0.9, Ccr<50) and D(n=53; ABI<0.9, Ccr<50). The mean follow up period was 620±270 days and evaluated the major cardiac adverse events included survival, stroke, acute coronary syndrome, and heart failure. Results: as shown in Figure. Conclusions: The present data may conﬁrm the possibility that combination of these respectively independent risk factors of arteriosclerosis disease (mild renal insufﬁciency and ABI low value) predicts long term outcomes. ACC_2006_8_VascularDisease.indd 294 1/4/06 5:20:52 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 295A Vascular D isease, H ypertension, and P revention POSTER SESSION 912 Peripheral Arterial and Carotid Disease Pathophysiology Sunday, March 12, 2006, 9:00 a.m.-12:30 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 912-191 Simultaneous Application of Prostaglandin E1 Enhances the Arteriogenesis by Sustained-release of Basic Fibroblast Growth Factor in the Rabbit Hindlimb Ischemic Model Yoshio Arai, Akira Marui, Keiichi Hirose, Hitoshi Sakaguchi, Yuhong Huang, Shyamal Chandra Bir, Tadashi Ikeda, Yasuhiko Tabata, Masashi Komeda, Kyoto University Graduate School of Medicine, Kyoto, Japan, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan Background:Therapeutic angiogenesis/arteriogenesis by basic ﬁbroblast growth factor (bFGF) is an effective therapy for severe limb ischemia, while Prostaglandin E1 (PGE1) is a potent vasodilator that improves tissue blood perfusion. In patients with severe/critical limb ischemia, PGE1 cannot be discontinued while PGE1 might suppress arteriogenesis by bFGF. However, little has been reported on this clinically important issue. Purpose of this study is to investigate the optimal timing of PGE1 administration in therapeutic angiogenesis. Methods: Gelatin hydrogel was used as a sustained-release carrier for bFGF. Two weeks after the excision of the right femoral artery of rabbits, the animals were divided into 5 groups (n= 8/group): no treatment (Group A), i.v. injection of 8µg PGE1 for 14 days (Group B), single intramuscular injection of 50µg bFGF into the right thigh muscles (Group C), simultaneous application of bFGF and PGE1 in the same manner as for groups B and C (Group D) and 14-day injection of PGE1 which starts 14 days after injecting bFGF in the same manner as for group C (Group E). The number of CD31 positive vessels was counted to evaluate vascular density, and the number of �-smooth muscle actin positive vessels to evaluate vascular maturity. Results: See table. Conclusions: Combined application of PGE1 and bFGF may be more effective than their individual use. Optimal timing of adjuvant PGE1 administration is during (i.e., not after) therapeutic angiogenesis by bFGF. Group A Group B Group C Group D Group E Calf blood pressure ratio (%) 0.66±0.05† 0.73±0.05† 0.80±0.08* 0.89±0.03* 0.81±0.06* Microangiographic score 0.17±0.02 † 0.49±0.05* † 0.56±0.05* † 0.65±0.01* 0.56±0.02* † Vascular density (vessels/mm2) 116±8 † 148±8* † 182±6* † 236±5* 194±4* † Vascular maturity (vessels/mm2) 3.7±0.4 † 4.0±0.4 † 7.0±0.6* † 12.2±0.4* 9.2±0.9* † *p<0.05 vs. group A . † p<0.05 vs. group D. 912-192 Parathyroid Hormone, Endothelial Dysfunction and Arterial Stiffness in Chronic Renal Disease Jose Jg Lima, Valeria Hong, Luis A. Bortolotto, Vanda Jorgetti, Fernanda Consolin- Colombo, Kaleizu Rosa, Eduardo M. Krieger, Jose AF Ramires, Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil, Hospital das Clínicas, University of Sao Paulo Medical School, Sao Paulo, Brazil Background: secondary hyperparathyroidism (SHPT), high serum phosphate and Ca x P product are associated with cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). A more direct role played by PTH itself in this context remains controversial. We evaluated the relationship between serum PTH and endothelial dysfunction and arterial stiffness in CKD patients treated by maintenance hemodialysis with varying degrees of SHPT. Methods: vascular reactivity and arterial stiffness were determined in 31 CKD patients (46 ± 13 yo, 20 males, 15 caucasians on HD for 78 ± 39 months) and in 12 age, gender and race matched controls. Brachial artery diameter was recorded by vascular ultrasonography scan at baseline and after both reactive hyperemia and 4mg of sublingual nitrate, to analyze respectively the endothelium-dependent and -independent responses. Large vessel distensibility was evaluates by carotid distension using a high deﬁnition echotrecking device. Smokers, diabetics and patients with CV disease were excluded. Results: compared to controls, both endothelium dependent (5.8 ± 4.3% vs 11.6 ± 5.4%, p< 0.001) and independent (11.7 ± 7.6% vs 23 ± 7.5%, p< 0.001) vasodilation were reduced in CKD patients. Endothelial-dependent vasodilation was negatively correlated with PTH (r- 0,416, p< 0.05) and age (r= -0.365, p< 0.05) and positively with endothelium- independent vasodilation (r= 0.483 p< 0.01). Blood pressure, dialysis duration and serum levels of Ca, P and Ca x P product, total cholesterol and triglycerides did not inﬂuence endothelium-dependent function. On multivariate analysis, only PTH and endothelium- independent vasodilation remained signiﬁcantly associated with endothelial dysfunction (p< 0.01). Carotid distension correlated negatively with age (r= -0.681, p< 0.01) and Ca x P product (r= -0.496, p< 0.01) but was not inﬂuenced by PTH. Conclusions: PTH adversely affects endothelial function in CKD patients with SHPT while large vessel distension is inﬂuenced by the Ca x P product. This result suggests a dual mechanism of vascular aggression in SHPT: an endothelial effect mediated by PTH and a media/adventitial effect linked to alterations of mineral metabolism. 912-193 Diabetic Plaque Inﬂammation and Neovascularization Are Associated With Increased Reparative Collagen Content: Implication for Plaque Progression in Diabetic Atherosclerosis K-Raman Purushothaman, Valentin Fuster, Marc Sirol, William N. O’Connor, Samin K. Sharma, Randolph Hutter, Pedro R. Moreno, Mont Sinai School of Medicine, New York, NY Background: Our group has documented increased inﬂammation, neovascularization and intraplaque hemorrhage (IPH) in atherosclerotic lesions from patients with diabetes mellitus (DM). This sustained injury may induce a reparative response increasing collagen synthesis and leading to disease progression. To evaluate this process of injury-repair, we quantiﬁed reparative collagen (Type III) content in plaques form patients with DM and compared to plaques from patients without DM. Methods: Thirty-six lipid-rich diabetic plaques were compared to 32 lipid-rich non-diabetic plaques obtained from the aorta at the time of autopsy. Inﬂammation, neovessels and IPH were quantiﬁed as previously described (Circulation 2004; 110:2032-8). Reparative collagen III content was quantiﬁed by computerized planimetry using Picro-Sirius Red stain polarizing microscopy. Results: Inﬂammation, neovessels and reparative collagen III were signiﬁcantly increased in DM when compared to non-DM plaques (P<0.001), as shown in bar graph and Figure). Reparative collagen III content (yellow arrows) was also increased in plaques with IPH (P<0.05). Finally, reparative collagen III content correlated with total microvessel content (r=0.55; P<0.0001). Conclusion: The increased inﬂammation and neovascularization process in DM is associated with an increased reparative process mediated by collagen III. This active reparative process may contribute to plaque progression in diabetic atherosclerosis. 912-194 Chronic Total Occlusions (CTO) in the Iliofemoral Arteries: Initial and Long-Term Outcomes Lou Vadlamani, Khusrow Niazi, Chin Kim, William A. Gray, Cardiovascular Medicine, Marietta, GA, Crawford Long Hospital, Atlanta, GA Background: To evaluate the initial and long-term success in treating chronic total occlusion (CTO) in iliac (IA) and superﬁcial femoral arteries (SFA) utilizing current technologies. Methods: 144 consecutive CTO procedures were retrospectively analyzed and classiﬁed according to location. Therapeutic success was deﬁned as the intra-luminal wire placement of a wire distal to the CTO, and a < 20 % residual stenosis at the end of the procedure. Procedural complications were deﬁned as (i) access hemorrhage prolonging hospitalization (ii) complications requiring surgery (distal embolization, dissection, perforation). Patency was assessed at 6 month intervals with Doppler ultrasound; restenosis was deﬁned as a greater than 50 % reduction in lumen diameter. ACC_2006_8_VascularDisease.indd 295 1/4/06 5:20:52 PM 296A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n Results: CTO were present in 59 iliacs IA and 85 SFAs. IA were successfully recanalized in 100% of the patients, with a 3.7% complication rate (2 access bleeds). Reentry devices were used in 31/59 (52 %) of the procedures and all lesions were stented. 6 and 12 month primary patency rates were 83.3% and 76% respectively and secondary patency rates were 98% and 96 % respectively. 80/85 (94%) SFA lesions were successfully treated with a 5% complication rate (2 access bleeds and 2 distal embolizations). 10/80 (12.5 %) lesions were treated with balloon angioplasty alone, 58/80 (72.5%) were stented, and the remaining 12/80 (15%) had atherectomy with adjunctive balloon angioplasty. 6 and 12 month primary patency rates were 73% and 68 % respectively with secondary patency rates of 73% and 64 %. For SFA CTO lesions < 10 cm (61/85 - 76 %) the 6 and 12 month primary patency rates were 82% and 79% respectively with secondary patency rates of 82 % and 73%. For CTO >10 cm (19/85 - 24%) primary patency rates were 42 % and 32 % respectively, with secondary patency rates of 64% and 55 % at 6 and 12 months respectively. Conclusions: These ﬁndings suggest CTO of the IA and SFA can be treated using endovascular techniques with high initial success rates and, minimal complications. Mid- and long-term patency appear robust for all CTO in IA and short (<10 cm) CTO in the SFA. SFA CTO (>10cm) patency rates continue to be suboptimal in spite of successful early successes rates of recanalization. 912-195 Comparison of MRI Based Measurement of Atherosclerotic Plaque Burden in Patients With and Without Cardiovascular Disease Hiroaki Taniguchi, Karen B. Weinshelbaum, Silvia H. Aguiar, Venkatesh Mani, Dan D. Samber, Rob van der Geest, J. H.C. Reiber, Frank Macaluso, John E. Postley, Zahi A. Fayad, Mount Sinai school of Medicine, New York, NY, Leiden University, The Netherlands Background:Previous studies have reported that atherosclerosis is a systemic disease. MRI based quantitative measurement may be a useful non-invasive test to aid secondary prevention of cardiovascular disease. The purpose of this study was to use MRI for quantitative analysis of atherosclerosis and to compare MRI based measurements of atherosclerosis in patients with and without cardiovascular disease (CVD), where CVD is deﬁned as coronary artery disease and stroke. Methods:114 patients underwent high resolution Black-blood MRI. For each patient, 12-24 carotid and 32-48 aortic images were acquired. Of those 114 patients, 38 had CVD (mean age 66±8 years old, 68% male), and 76 were age and gender matched control patients without CVD (mean age 65±7 years old, 60% male). Because the patients with CVD were under standard care (mean duration : 44 month), the percentage of patients taking lipid lowering or anti-hypertensive drugs was signiﬁcantly higher in the patients with CVD.(89% vs. 62%, P<0.05, 68% vs. 39%, P<0.01, respectively) There were no signiﬁcant differences in lipid proﬁles between the patients with and without CVD. The inner and outer edges of the vessel wall were traced manually and vessel wall thickness (VWT) and wall area (VWA) were calculated in the common carotid artery (CCA) and thoracic aorta (Ao). Results:VWA of Ao and CCA in the patients with CVD were signiﬁcantly greater than those of the patients without CVD (1.14±0.29 vs. 1.00±0.27, P<0.05, 0.24±0.07 vs. 0.21±0.06, P<0.01, respectively) VWT of Ao and CCA in the patients with CVD were also greater than those of the patients without CVD (1.49±0.28 vs. 1.35±0.28, P<0.05, 0.95±0.20 vs. 0.83±0.16, P<0.01, respectively) Conclusions:This study revealed that patients with CVD even under standard care had greater VWA and VWT than age and gender matched patients without CVD. MRI based non-invasive measurements of atherosclerotic plaque burden may be an important parameter to monitor atherosclerosis and aid in secondary prevention. POSTER SESSION 913 Genetics: Populations Sunday, March 12, 2006, 9:00 a.m.-12:30 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 913-196 Atherosclerosis Regression With Selective Estrogen Receptor Modulator Therapy: An In Vivo Study of Raloxifene by Magnetic Resonance Imaging and Micro- Computed Tomography Brian G. Choi, Gemma Vilahur, Mohammed Urooj Zafar, Luis Cardoso, Constantin A. Novoselsky, Daniel Yadegar, Barbara Bonacasa, Juan F. Viles-Gonzalez, Mitchell B. Schafﬂer, Valentin Fuster, Juan J. Badimon, Mount Sinai School of Medicine, New York, NY Background: Estrogen therapy is associated with increased cardiovascular events in post-menopausal women, but post-hoc analysis from an osteoporosis trial suggests that the selective estrogen receptor modulator raloxifene decreases cardiovascular events in high-risk women. The ongoing Raloxifene Use for the Heart (RUTH) study seeks to conﬁrm this beneﬁt, but the mechanism is unclear. We assessed the hypothesis that raloxifene mediates changes in atherosclerotic lesions that enhance plaque stability. Methods: Atherosclerosis was induced in ovariectomized New Zealand White rabbits (n=42) by a combination of 2 aortic endothelial balloon denudations and 9-months atherogenic diet (0.2% cholesterol). Rabbits were then imaged by magnetic resonance (MRI) for baseline atherosclerosis measurement and randomized into placebo (PBO, n=18) or raloxifene 35-60 mg/kg/d (RLX, n=24). After 6 months of continued atherogenic diet, rabbits underwent repeat MRI and then sacriﬁce for ex vivo micro-computed tomography (µCT) and molecular analysis. Results: RLX signiﬁcantly reduced atherosclerotic vessel wall area vs. baseline by -5.5 ± 0.9% (p=0.04) with no signiﬁcant change in PBO. µCT showed similar total vascular calciﬁcation between the groups, but calciﬁcations in RLX were less nodular and more concentrically organized (mean calciﬁc arc angle 64.3 ± 6.8° vs. 33.4 ± 6.6° in PBO, p<0.01). Immunohistologic analysis of the lesions showed no difference in macrophage content but reduced activity as assessed by matrix metalloproteinase MMP-1 expression (RLX 19.9 ± 2.5% vs. PBO 38.3 ± 7.6%, p<0.01). Analysis for inﬂammation by Western blot revealed >60% reduction in cyclooxygenase-2 and monocyte chemoattractant protein-1 expression (both p<0.01) in RLX vs. PBO. Oil Red O staining for lipid deposition is pending. Conclusion: Our data show that treatment with raloxifene results in regression of established atherosclerotic lesions, enhanced formation of calciﬁcation in a pattern associated with plaque stability, reduced MMP activity, and decreased inﬂammation. These observations suggest lesion stabilization. Whether these changes translate to clinical beneﬁt will be answered by RUTH. 913-197 The Effects of Caffeine on the Inducibility of Atrial Fibrillation Abdul Rashid, Mujahid Hines, Benjamin J. Scherlag, William S. Yamanashi, William Lovallo, University of Oklahoma, Oklahoma City, OK, Veterans Affairs Medical Center, Oklahoma City, OK Background: It is believed that caffeine consumption is linked to atrial arrhythmias, however, there is a relative lack of evidence to support the assertion. The purpose of our study was to investigate whether caffeine alter the propensity for atrial ﬁbrillation (AF) in an experimental model. Methods: Caffeine (Caffeine Na Benzoate, 50:50 mixture) was administered intravenously at 1mg/kg, 3mg/kg and 5mg/kg doses in dogs producing serum levels of 2-4, 5-7, and 8-10 µg/ml. To simulate focal AF, premature stimulation from the right superior pulmonary vein (RSPV) was delivered at 2x, 4x and 10x threshold at a rate of 180/min (S1-S2 = 330 msec) without and then with low-level stimulation of ganglionated-plexi (GP) at the entrance of the RSPV. The window of vulnerability (WOV), a measure of the propensity for AF inducibility was determined by the longest S1-S2 minus the shortest S1-S2 which induced AF. The cumulative WOV is the sum of the individually determined WOVs. Results: At each serum level of caffeine the cumulative WOV was lower without rather than with GP stimulation compared to control (Figure, below) The cumulative WOV for both the stimulated, i.e., predisposed to AF and non-stimulated, i.e., normal groups exhibited a signiﬁcantly lower average at each serum level of caffeine as compared to that exhibited by the control group (p≤ 0.003-0.02). Conclusions: The presence of caffeine may result in an unexpected reduction in the propensity for AF in normal individuals and in those with a predisposition for AF. 913-198 Olmesartan Inhibits NF-κB Activity and Attenuates Hypoxia-Induced Left Ventricular Remodeling in Apolipoprotein E-Knockout Mice Chika Yamashita, Tetsuya Hayashi, Daisuke Nakano, Tatsuhiko Mori, Koichi Sohmiya, Nobuaki Okuda, Yoshikatsu Okada, Yasushi Kitaura, Yasuo Matsumura, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan, Osaka Medical College, Takatsuki, Japan Background: Hypoxia might be involved in the development of left ventricular (LV) remodeling. We have reported that chronic hypoxia exacerbated atherosclerosis in apolipoprotein E-knockout (apoE-KO) mice. The aim of this study was to evaluate the effect of angiotensin II receptor blocker on LV remodeling in apoE-KO mice exposed to hypoxia. Methods: Male apoE-KO mice (n=33) and wild-type mice (n=12) at 15 weeks of age, kept under hypoxia (oxygen, 10.0 +/- 0.5%), were treated with olmesartan (3mg/kg/day) or vehicle for 3 weeks. Ultrastructure of LV myocardium and percent ﬁbrosis (%Fibrosis) in the interstitium were examined, and nuclear factor-κB (NF-κB) activity in LV myocardium was evaluated by gel shift assay. Results: Hypoxia signiﬁcantly increased interstitial ﬁbrosis in apoE-KO mice (Figure). Ultrastructural degeneration, hypertrophy of cardiomyocytes, and NF-κB activity tended to be increased by hypoxia in all animals. These changes were more prominent in apoE- KO than wild-type mice. Olmesartan effectively suppressed NF-κB activity and preserved ﬁne structure of LV myocardium independent of blood pressure. Conclusions: In apoE-KO mice, olmesartan inhibits NF-κB activity and attenuates ACC_2006_8_VascularDisease.indd 296 1/4/06 5:20:53 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 297A Vascular D isease, H ypertension, and P revention hypoxia-induced LV remodeling, which might suggest the important role of renin- angiotensin-aldosterone system in hypoxic condition. 913-199 Coadministration of the V2 Receptor Antagonist Tolvaptan and B-Type Natriuretic Peptide Enhances Water and Sodium Excretion Without Adversely Affecting Renal Function: A Physiologic Approach to Sodium and Water Retention in Experimental Heart Failure Lisa C. Costello-Boerrigter, Guido Boerrigter, John A. Schirger, John C. Burnett, Jr., Mayo Clinic and Mayo Clinic College of Medicine, Rochester, MN Background: Renal dysfunction is increasingly recognized as a major prognostic factor in heart failure (HF). Importantly, diuretic therapy may adversely affect renal function. Therefore, diuretic strategies that maintain or enhance renal function appear warranted. Tolvaptan (TLV) is a V2-receptor antagonist and thus counteracts the water reabsorption mediated by arginine vasopressin in renal collecting duct cells. B-type natriuretic peptide (BNP) has important renal hemodynamic and tubular enhancing actions. We hypothesized that coadministration of TLV and BNP would cause a potent diuresis without adversely affecting renal function. Methods: Severe HF was induced in three groups of dogs (n=6 each) by tachypacing. On day 11 cardiorenal function was assessed in an acute study. One group received TLV alone (0.1 mg/kg IV bolus), whereas the two other groups received a low or high dose infusion of BNP (10 and 50 ng/kg/min, respectively) in addition to TLV . *p<0.05. Results: TLV alone increased urine ﬂow from 0.07±0.01 to 0.48±0.09* mL/min, while urinary sodium excretion (UNaV), glomerular ﬁltration rate (GFR), renal blood ﬂow (RBF), mean arterial pressure, and cardiac output did not change. Coadministration of TLV and low-dose BNP increased urine ﬂow from 0.11±0.03 to 1.23±0.48* mL/min and UNaV from 1.83±0.6 to 3.75±1.06* uEq/min (*compared to TLV alone). TLV plus high- dose BNP further increased urine ﬂow from 0.17±0.07 to 2.58±0.47* mL/min and UNaV from 1.3±0.6 to 77±23* uEq/min, while decreasing both proximal and distal fractional Na reabsorption (all *compared to both other groups). GFR and RBF were preserved and indeed tended to increase with TLV plus high-dose BNP. None of the regimens changed plasma Na, K, or osmolality. Conclusions: TLV alone acts primarily as a physiologic aquaretic without changing UNaV. BNP coadministered with TLV dose-dependently increased the urine ﬂow and UNaV. All three diuretic regimens did not adversely affect GFR and renal hemodynamics; indeed, TLV with high-dose BNP tended to increase GFR and RBF. We conclude that TLV alone or in combination with BNP may be a physiologic renal enhancing strategy in severe HF warranting further investigation. 913-200 Enhanced Expression of Leptin, Leptin Receptor, and Leptin Signaling in the Failing Human Heart Kenneth R. McGafﬁn, Benjamin Burkhead, Gregory Gibson, Charles McTiernan, University of Pittsburgh Medical Center, Pittsburgh, PA Background: Obesity and metabolic syndrome contribute to the development of cardiovascular disease. Fat secretes biologically active molecules that may mediate inﬂammatory and atherosclerotic processes. Leptin (OB) is a fat derived hormone that initiates signal transduction via Jak/STAT3 and SOCS3 through binding to its long-form receptor (OBR). OB is increased in the circulation of patients with myocardial infarction and heart failure (HF), independent of obesity. This study examines the cardiac expression of OB, OBR, and OBR signaling in patients with end stage HF. Methods: Left ventricular (LV) tissue was obtained from 8 non-failing (NF) and 14 end stage failing (F) human hearts at the time of cardiac transplantation. Diagnosis of F hearts were 50% idiopathic, 50% ischemic. Levels of mRNA and protein for OB and OBR were determined by real time PCR (RT-PCR) and immunoblot, and human SOC3 by immunoblot, with samples normalized to GAPDH. Results reported are fold-induction +/- SEM relative to NF, compared by t-test. Immunoﬂuorescent imaging was used to localize expression of OB and OBR in cardiac tissue. To assess the response of cardiac tissue to leptin, transiently cultured mouse heart samples were challenged with leptin (0.1nM to 100nM) for 0-120 minutes and resultant SOCS3 mRNA levels were measured (RT-PCR). Results: Versus NF, F hearts showed induction of OBR mRNA (4.5+/-0.1 fold, p<0.01) and protein (5.1+/-1.2 fold, p<0.05), and OB mRNA (6.1+/- 0.1 fold, p<0.05) and protein (2.1+/-0.2 fold, p<0.01). Immunoﬂuorescence localized expression of both OB and OBR to the cardiomyocyte. Versus NF, F hearts showed induction of SOCS3 (4.3+/-1, p<0.02). Mouse cardiac tissue responded to 12 nM leptin with a 3.5 fold induction of SOCS3 mRNA, indicating an active cardiac response to leptin. Conclusions: The failing human heart produces signiﬁcant amounts of leptin and increased expression of the OBR long form. The increased expression of downstream leptin signaling intermediates (SOCS3) in the failing heart, and induction of SOCS3 by leptin in normal mouse cardiac tissue, suggests that leptin may play role in the molecular mechanisms underlying heart failure. 913-201 Genotype of the Beta-Adrenergic Receptor Polymorphism Was a Strong Risk Factors for Neurally Mediated Syncope Jin-Shik Park, Dae-Won Sohn, Byung-Hee Oh, Young-Bae Park, Yun-Shik Choi, Hyo- Soo Kim, Seoul National University Hospital, Seoul, South Korea Background: Neurally mediated syncope(NMS) is a common disease which is associated increased sympathetic discharge and hypersensitive mechanoreceptor of the heart. Sympathetic discharge takes effect through adrenergic receptors(AR) and several common AR polymorphisms result in functional changes. We investigated the association between the AR polymorphisms - β1 Gly389Arg and β2 Gln27Glu - and neurally mediated syncope. Methods:We identiﬁed the genotype at position 389 of the β1 AR and 27 of the β2 AR in 98 consecutive patients who had undergone head-up-tilt table test under the suspicion of the NMS. Polymerase chain reaction and restriction enzyme digestion method was used for genotyping. NMS was diagnosed by the pre-speciﬁed criteria for head-up-tilt table test. Results:Average age of the patient was 41±17 and 44 patients (44%) were male. Neurally mediated syncope was diagnosed in twenty one patients. The genotype distribution of the β1 AR was ArgArg 68%, ArgGly 28%, GlyGly 4% and that of the β2 AR was GlnGln 72%, GluGln 24%, GluGlu 3%. The genotype distributions were in the Hardy-Weinberg equilibrium. The patients who have Glu allele at the β2 27 position showed a tendency to have higher prevalence of NMS(43% vs 23%, p = 0.095) in univariate analysis. In combined genotype analysis, the simultaneous presence of the β1 Gly389 allele carrier and β2 Glu27 allele was the strongest risk factor of the NMS in the multivariate analysis including age, sex, diabetes, hypertension and use of betablocker. (Odds ratio = 3.0, 95% Conﬁdence interval 1.052-8.553) Conclusions: The combination of AR polymorphisms genotype (β1 Gly389 allele carrier state and β2 Glu allele carrier state) was a strong risk factor for NMS. POSTER SESSION 914 Lipids, Lipoproteins and Atherosclerosis Sunday, March 12, 2006, 9:00 a.m.-12:30 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 914-202 Effects of Single Nucletide Polymorphisms of Atherosclerosis Related Genes on Response to HMG- CoA Inhibitors After Acute Myocardial Infarction Yasuhiko Sakata, Hiroshi Sato, Hiroya Mizuno, Daisaku Nakatani, Masahiko Shimizu, Shin-ichiro Suna, Masatsugu Hori, Osaka University Graduate School of Medicine, Suita, Japan Background: Several reports have suggested that presence of single nucleotide polymorphisms (SNPs) might affect the response to drugs in patients. Methods: We sought to investigate the inﬂuence of SNPs on response to HMG-CoA inhibitors in patients with acute myocardial infarction (AMI). We prospectively investigated consecutive 1586 AMI patients who were registered in Osaka Acute Coronary Insufﬁciency Study (OACIS) and agreed to the the present study. In relation to the analysis of 87 SNPs in 73 candidate genes associated with inﬂamation, atherosclerosis and metabolism of lipid and glucose, the incidence of all cause death and non-fetal myocardial infarction were compared between patients treated with and without statin after AMI. Results: Among the SNPs investigated, alpha ﬁbrinogen(AFGN) 934 AA/AG, beta 2 adrenoceptor(B2AR) 46AA/AG, Endothelin-1 (ET1) 5665 GG, Hepatic Lipase (HL) 480 CC/CT, Tumor Necrosis Factor Beta (TNFB) 252GG/GA, P22phox 242 CC, Thrombopoietin(TP) 5713 AA polymorphisms were associated with better prognosis in patients with statin treatment compared with AFGN GG, B2AR 46GG, ET1 5665 GT/ TT, HL 480 TT, TNFB 252AA, P22phox 242 CT/TT, TP 5713 AG/GG polymorphisms, respectively. In particular, while the polymorphism of either TNFB (252GG/GA) or AFGN (934 AA/AG) was associated with increased incidence of all-cause death, statins decreased the mortality ratio to the same level of the patients without each polymorphism. In contrast and interestingly, no further beneﬁcial effects of statin treatment on secondary prevention after AMI were observed in patients with TNFB 252AA and AFGN 934GG polymorphism, suggesting that the prescription of statins were not necessarily associated with better outcome in all patients after AMI. Conclusions: These data suggested that effectiveness of statins after AMI were changed according the the presense or absence of SNPs. Investigation of SNPs in candidate genes may provide us more information of drug response and better clinical outcomes. ACC_2006_8_VascularDisease.indd 297 1/4/06 5:20:53 PM 298A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n 914-203 On-treatment Levels of HDL-C and the Ratio of LDL- C/HDL-C as Predictors of Cardiovascular Events in the Treating to New Targets (TNT) Study Philip Barter, Antonio Gotto, John LaRosa, Scott Grundy, John Kastelein, Vera Bittner, Jean-Charles Fruchart, on behalf of the TNT Steering Committee and Investigators, The Heart Institute, Sydney, Australia Background and Aims: The TNT study showed that intensive lipid-lowering therapy with atorvastatin 80 mg/day provides signiﬁcant clinical beneﬁt beyond that afforded by treatment with atorvastatin 10 mg/day in patients with stable coronary heart disease (CHD). The current analysis investigates the relationship between major cardiovascular events (MCEs) and on-treatment levels of HDL-C and the ratio of LDL-C/HDL-C. Methods: Patients were randomized to treatment with atorvastatin 80 mg or atorvastatin 10 mg and followed for a median of 4.9 years. The primary end point was the occurrence of a ﬁrst MCE, deﬁned as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. Results: We previously reported the direct relationship between lower on-treatment LDL- C and MCEs. We now report the following univariate relationships: MCEs are inversely related to on-treatment HDL-C, and directly related to the ratio of LDL-C/HDL-C (both P<0.0001) (see Table). While the HDL-C relationship appeared attenuated in the 80 mg group, the ratio was not only a strong positive predictor of events in both groups, but for any given LDL-C/HDL-C ratio, the event rate was similar in the two groups. Conclusion: While the control of LDL-C remains a pivotal focus of prevention, our results suggest that HDL-C levels and the ratio of LDL-C/HDL-C provide additional prognostic information and should be considered potential targets for future drug therapy. 914-204 Profound Increase of HDL-c Levels (>50%) With Long- Term Niacin Treatment Leonard M. Keilson, Scott Bieswenger, Maine Center for Lipids and Cardiovascular Health, Scarborough, ME, Maine Medical Center, Portland, ME Background: HDL provides a mechanism of reverse cholesterol transport with higher levels of HDL-c resulting in reduced heart disease risk. Niacin and extended release (ER) niacin are reported to raise HDL-c levels by 30% over pre-treatment levels. Extended release (ER) niacin combined with a statin (niacin/lovastatin-Advicor) in a 12 month trial increased HDL-C by 30% at 16 weeks and 41% at 52 weeks. This phenomenon was deﬁned as “HDL creep”. Long-term effects of niacin treatment may occur even beyond the cessation of therapy. The Coronary Drug Project utilized 5 years of niacin therapy as an intervention and beneﬁcial effects were noted at least 9 years beyond the termination of the trial. The Maine Center for Lipids has provided ER niacin therapy for 270 patients in treatment periods as long as ten years continuously. The purpose of this study was to describe ER niacin treated patients with a greater than 50% increase in HDL over baseline. These patients are deﬁned as niacin “hyper-responders”. Methods: The Maine Center for Lipids medical data base identiﬁed ER niacin treated patients with more than 3 ofﬁce visits including baseline and “on-treatment” values and an HDL level greater than 50% of the baseline level. 11,000 patient records over 15 years were screened. Data elements including BMI, blood sugar, medication usage were collected; manual chart review was performed. Results: 13 of 270 ER niacin treated patients were identiﬁed as “hyper-responders” There were an average 22 ofﬁce visits per patient over 5 years (sd+2.7; median 7 years). Baseline values included: HDL 32.2 (sd+11), triglycerides 288 (+71). Average increases in HDL were 90% (sd+33%, range: 52%-153%, median: 63%). Other characteristics: 4% were diet controlled diabetics; 69% were treated with statin therapy for the entire treatment interval; 100% were treated with statins for at least 2 years. Weight fell in this population by 4% and triglyceride level 43% from baseline. Conclusions: m5 % of an ER niacin treated population achieved HDL levels 50% greater than baseline. Hyper-responders experienced a reduction in body weight, triglycerides and were statin treated. 914-205 Lipoprotein Subclasses, Hydroxy Fatty Acids, and the Inﬂammatory Response in Metabolic Syndrome Patients Robert S. Rosenson, Anna L. Huskin, David A. Wolff, Northwestern University, Chicago, IL Background: Elevated levels of inﬂammatory markers identify metabolic syndrome subjects at increased cardiovascular risk. We are unaware, however, of any studies investigating changes in fasting lipoprotein subclasses, hydroxy fatty acids (OH-FA) and inﬂammatory markers in metabolic syndrome subjects. Methods: Randomized, double blind, placebo-controlled trial to examine the effects of fenoﬁbrate (160mg/d) therapy on fasting levels of inﬂammatory markers among 55 metabolic syndrome subjects with high fasting triglycerides (≥ 150 and < 600 mg/dL). Results: Treatment with fenoﬁbrate lowered circulating levels of ICAM-1, VCAM-1, TNF receptor 1, ﬁbrinogen, CRP, and OH-FA (Table). In multivariate adjusted stepwise regression models, changes in ICAM-1 (p<0.05), VCAM-1 (p<0.002) and CRP (p<0.005) correlated with low baseline HDL cholesterol. Changes in TNF receptor 1 (p<0.02) and CRP (p<0.001) correlated with changes in OH-FA. ICAM-1 correlated with changes in VLDL particle numbers (p=0.005). Changes in TNF-R1 were inversely correlated with changes in hypertension status (p=0.005). Conclusions: In hypertriglyceridemia subjects with the metabolic syndrome, fenoﬁbrate therapy reduced inﬂammatory markers, and these changes were associated with low HDL cholesterol levels and changes in OH-FA. Effects of Fenoﬁbrate on Inﬂammatory Markers Placebo Fenoﬁbrate Baseline Treatment % ∆ Baseline Treatment % ∆ P-Value VCAM-1(ng/mL) 543.2 ± 16.5 525.1 ± 17.5 -3.3 548.5 ± 13.7 493.9 ± 11.9 -10.1 <0.001 ICAM-1(ng/mL) 409.3 ± 16.4 401.2 ± 16.2 -2.0 382.1 ± 15.4 323.8 ± 14.2 -15.6 <0.001 TNF-R1(ng/mL) 3.91 ± 0.19 3.95 ± 0.12 +1.0 3.80 ± 0.11 3.72 ± 0.10 -2.1 <0.05 Fibrinogen(mg/ L) 3.49±0.16 3.63±0.15 +4.4 3.35±0.16 3.02±0.13 -6.6 0.073 CRP(mg/L) 2.4 (2.0-3.1) 2.2 (1.6- 2.7) -9.1 2.6 (1.4- 3.1) 1.9 (1.1- 2.6) -27.6 0.02 OH-FA(umol/L) 1.15±0.06 1.24±0.07 +8.6 1.15±0.07 0.95±0.05 -12.1 <0.005 914-206 Do Omega-3 Fatty Acids/Fish Oil Reduce Mortality in Patient without Coronary Artery Disease? Vinod K. Raxwal, Peter Tadros, James Vacek, Charles Porter, David Wilson, Robert Candipan, Kansas University Medical Center, Kansas City, KS Background: Omega-3 fatty acids (OFA) have been shown in epidemiological and clinical trials to reduce the incidence of cardiovascular disease. However effect of OFA on mortality has not been well studied in patient without coronary artery disease (CAD). Methods: We studied 2870 patients taking OFA/ﬁsh oil and compared with 27811 patients not taking OFA. Patients were followed from 1998 through April, 2005. End point was all cause mortality. Patients were stratiﬁed into two groups: with and without coronary artery disease. Survival curves of patients grouped by CAD status were calculated by the Kaplan-Meier method and compared with the log-rank test. Logistic regression model was used to evaluate the signiﬁcance of OFA usage after adjusting for diabetes, HTN and hypercholesterolemia. Results: Mean age of the studied population was 59±16 years with a mean follow up of 3±2 years. Prevalence of HTN was 39%, 18% had CAD, 12% had diabetes and dyslipidemia was prevalent in 38% of the patients. Baseline characteristics in both the groups were comparable. Mean EF was 53 ± 12% in patients taking OFA and 55 ± 11% not taking OFA. During the follow up 3062 patients died, 11% (n= 2958) of the patients not taking OFA, versus 4% (n=104) on OFA (p<0.001). Conclusions: Patients on omega-3 fatty acids had a better survival in comparing to patients not taking any ﬁsh oil supplements. Improved survival was observed in both the groups with and without CAD suggesting addition of ﬁsh oil supplements to diet should be recommended. 914-207 Regression of Coronary Atherosclerotic Plaques Induced by Pioglitazone in Patients With Type 2 Diabetes Mellitus or Impaired Glucose Tolerance: Results From a Randomized Prospective Study Using Intravascular Ultrasound Takashi Nakayama, Nobuyuki Komiyama, Masaki Yokoyama, Susumu Namikawa, Nakabumi Kuroda, Yoshio Kobayashi, Issei Komuro, Chiba University Hospital, Chiba, Japan, Saitama Medical School, Moroyama, Japan Background: It has been already reported that pioglitazone can attenuate atherosclerosis in aorta and carotid artery and can prevent cardiovascular events in diabetic patients. However, its beneﬁcial effects on coronary atherosclerosis have not been well clariﬁed. We examined whether pioglitazone clinically reduces the volume of coronary atherosclerotic plaque using intravascular ultrasound (IVUS). Methods: Twenty-six consecutive patients with type 2 diabetes mellitus (DM) or impaired glucose tolerance (IGT) undergoing percutaneous coronary intervention (PCI) were enrolled. Patients treated with insulin were excluded. IVUS images were recorded and echolucent plaques without angiographically signiﬁcant stenosis were selected at nonculprit coronary segments after PCI procedure. The patients were randomly assigned into 2 groups: group P (n = 13) taking pioglitazone 15 mg / day for initial 14 days after PCI and subsequent 30 mg / day during 6-month follow-up and group C (n = 13) as control. Volumetric analysis of targeted plaques (group P, n = 12; group C, n = 25) were performed with IVUS video images at baseline and 6-month follow-up. Plasma lipid proﬁles and levels of inﬂammatory markers were also measured at baseline and the follow-up. Results: In group P, plasma triglyceride level was signiﬁcantly decreased (141 ± 57 to 121 ± 61 mg / dl, p = 0.039) and high density lipoprotein cholesterol level was substantially increased (49 ± 10 to 59 ± 16 mg / dl, p = 0.011) without any signiﬁcant change in low ACC_2006_8_VascularDisease.indd 298 1/4/06 5:20:54 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 299A Vascular D isease, H ypertension, and P revention density lipoprotein cholesterol (LDL-C) level (126 ± 19 to 129 ± 13 mg / dl) after 6 months. High-sensitive C-reacting protein level tended to be decreased (1957 ± 2267 to 223 ± 221 ng / ml, p = 0.057). Plaque volume was signiﬁcantly reduced after 6 months in group P (101.3 ± 32.1 to 94.6 ± 33.6 mm3, p = 0.0003). However, no signiﬁcant change in those parameters was observed in group C during the follow-up. Conclusions: These results suggest that pioglitazone may induce regression of coronary atherosclerotic plaques in 6 months without LDL-C lowering as well as attenuation of inﬂammation in patients with DM or IGT, which may demonstrate a new beneﬁcial effect of pioglitazone on coronary atherosclerotic disease. POSTER SESSION 915 General Topics in Hypertension I Sunday, March 12, 2006, 9:00 a.m.-12:30 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 915-208 Darusentan Antihypertensive Effect in Patients With Resistant Hypertension Henry Black, Mahtouz El Shahawy, Robert Weiss, Georges Tannoury, Richard Marple, Michael Weber, Stuart Linas, George Bakris, Rush University Medical Center, Chicago, IL Background: Resistant hypertension (RHTN) is deﬁned by JNC 7 as the failure to achieve goal blood pressure (BP) in patients who are adhering to full doses of an appropriate 3-drug antihypertensive regimen that includes a diuretic. Darusentan is a selective ETA receptor antagonist that may provide antihypertensive effects via a mechanism of action independent of other classes of antihypertensive drugs when used as adjunctive therapy in patients with RHTN. Methods: Subjects with RHTN, adhering to ≥3 antihypertensives including a diuretic at documented full doses, were randomized 2:1 to blinded oral darusentan or placebo once daily. Following a 2-week placebo run-in, subjects underwent forced-titration of study drug every 2 weeks through doses of 10, 50, 100, 150, and 300 mg (10 weeks total). The co- primary endpoints were change from baseline in trough sitting systolic BP (SBP) to week 8 and to week 10 (150 and 300 mg doses, respectively, with adjustment for comparison of two doses) as compared to placebo. Secondary endpoints were change from baseline in trough sitting diastolic BP (DBP), mean 24-hour ambulatory SBP, and percent of subjects reaching JNC 7 SBP goals. Results: Of the 115 randomized subjects, 61% had diabetes and/or chronic kidney disease and 76 received darusentan. At baseline, mean SBP was 146.6 ± 14.8 mmHg and mean DBP was 80.0 ± 12.3 mmHg. At week 10 of darusentan treatment, the placebo- corrected change from baseline in SBP was -11.6 ± 3.3 mmHg (p=0.02) and -5.8 ± 2.3 mmHg (p=0.004) for DBP. Changes in mean ambulatory 24-hour placebo-corrected SBP and DBP were -9.2 ± 2.2 mmHg (p<0.001) and -7.2 ± 1.6 mmHg (p<0.001), respectively. In addition, 49% of darusentan-treated versus 28% of placebo-treated subjects (p=0.068) achieved JNC 7 SBP goals. Darusentan was well tolerated with no drug-related serious adverse events (AEs) or elevations in serum aminotransferase concentrations >2X ULN. The most frequent AE was peripheral edema (17%). There were 15 premature discontinuations (10 darusentan). Conclusions: Darusentan produced clinically and statistically signiﬁcant reductions in SBP and DBP in subjects with RHTN who were adhering to documented full doses of ≥3 antihypertensive drugs. 915-209 ACE Inhibitor Associated Cough: Difference Between Hypertension and Congestive Heart Failure Sripal Bangalore, Gayathri Kamalakkannan, Nisrine Koteich, Franz H. Messerli, St Lukes Roosevelt Hospital, New York, NY Background: Dry cough is a common, annoying adverse effect of angiotensin converting enzyme (ACE) inhibitors as a class. Cough in patients with chronic heart failure (CHF) can be multifactorial: medications, pulmonary congestion, etc. Methods: In a MEDLINE search from 1990 to the present we identiﬁed a total of 79 randomized controlled trials (RCT) dealing with the incidence of ACE inhibitor related cough. Of these, 33 studies with CHF or hypertension (HTN) and a sample size >100 on ACE inhibitors were chosen. Results: Among the study cohort on ACE inhibitors, 21,071 patients (mean age 66±9 years; 74% men) formed the CHF cohort and 9,323 patients (mean age 61±6 years; 60% men) formed the HTN cohort. The incidence of cough in the CHF cohort was 1.6 times higher than the HTN cohort (15.5% vs. 9.5%). Similarly in the control/placebo arm of these RCTs, the incidence of cough was higher in the CHF cohort than the HTN cohort (10% vs. 4.2%). On the contrary, the withdrawal of ACE inhibitor due to intolerable cough was higher in the HTN group than the CHF cohort (3.8% vs. 2.3%) (Figure). In both the cohorts, the incidence of cough was higher in women than in men (10% vs. 4.2% in CHF cohort; 8.3% vs. 6.7% in HTN cohort). Conclusions: The incidence of cough as reported in the RCTs is higher in patients with CHF than the HTN cohort attesting to multifactorial origin of cough in CHF. However, the withdrawal due to intolerable cough is higher in the HTN cohort, suggesting enhanced acceptance/tolerance of a nuisance adverse effect in the CHF cohort. 915-210 Coronary Heart Disease Events Preventable by Control of Blood Pressure and Lipids in U.S. Persons with Hypertension Nathan D. Wong, Victor A. Lopez, Simon Tang, Stanley S. Franklin, Rhys Williams, University of California, Irvine, Irvine, CA, Pﬁzer Pharmaceuticals, New York, NY Background: We estimated the coronary heart disease (CHD) events that could be prevented in U.S. adults with hypertension (HTN) from combined control of blood pressure (BP), low density lipoprotein-cholesterol (LDL-C), and high density lipoprotein-cholesterol (HDL-C). Methods: Among 1921 adults (projected to 85.2 million) aged 30-74 in the National Health and Nutrition Examination Survey 2001-2002 without known CHD, 676 (26.1 million or 30.6%) had HTN (BP >140/90 mmHg [130/80 mmHg if diabetes, DM] or on medication for HTN). Using Framingham risk algorithms, we projected the 10-year risk of CHD (and number of CHD events) given current risk factor levels, and if BP, LDL-C, and HDL-C were “controlled” to nominal and optimal levels by resetting Framingham coefﬁcients to those corresponding to goal levels; the difference in CHD events represented the events “prevented”. Results: The table below shows the number and proportion of CHD events “preventable” in 10 years by control of BP, LDL-C, and HDL-C, among men (M) and women (F) with HTN Uncomplicated (0 to 2 risk factors: age >45 male or >55 female, DM, smoking, HDL<40 mg/dl, and LDL-C >130 mg/dl (>100 mg/dl if DM)]), HTN Complicated (3-5 risk factors), HTN with metabolic syndrome, and HTN and DM: Group Number of CHD Events if BP and Lipids Not Controlled Number (Proportion, %) of CHD Events Prevented by Nominal Control of BP (<140/90 mmHg or <130/80 mmHg if DM) and Lipids (LDL<130 mg/dl or <100 mg/dl if DM, HDL>45 mg/dl) Number (Proportion, %) of CHD Events Prevented by Optimal Control of BP (<120/80 mmHg) and Lipids (LDL-C<100 mg/dl, HDL-C >60 mg/dl) HTN Uncomplicated M: 1.3 million F: 572,320 M: 441,817 (32.8%) F: 206,691 (36.1%) M: 1.0 million (74.3%) F: 439,129 (76.7%) HTN Complicated M: 645,024F: 151,824 M: 320,390 (49.7%) F: 71,705 (47.2%) M: 497,397 (77.1%) F: 119,012 (78.4%) HTN + Metabolic Syndrome without DM M: 758,844 F: 358,352 M: 279,380 (36.8%) F: 136,037 (38.0%) M: 593,173 (78.2%) F: 286,437 (79.9%) HTN + DM M: 373,472F: 112,251 M: 222,890 (59.7%) F: 48,729 (43.4%) M: 262,312 (70.2%) F: 83,579 (74.5%) Conclusion: In patients with HTN, one-third to half of CHD events could be potentially prevented by nominal control of BP and lipids and three-fourths of CHD events might be averted by optimal control. Clinical trials will be needed to conﬁrm these results. 915-211 Obstructive Sleep Apnea Impairs Arterial Stiffness in Hypertensive Patients: Potential Additive Effects to Atherosclerosis Luciano F. Drager, Luiz A. Bortolotto, Maria Cecília Lorenzi, Adelaide C. Figueiredo, Bruno C. Silva, Eduardo M. Krieger, Geraldo Lorenzi-Filho, Heart Institute (InCor) University of Sao Paulo Medical School, Brazil, Sao Paulo, Brazil Background: The impact of Obstructive Sleep Apnea (OSA) on vascular properties in comparison to other cardiovascular diseases has not been previously reported. We hypothesized that severe OSA impairs arterial stiffness, measured by pulse wave velocity (PWV), in patients with hypertension (H). Methods: All participants were submitted to a polysomnography. We studied four groups depending on the presence of OSA and H. The groups were matched for age, body ACC_2006_8_VascularDisease.indd 299 1/4/06 5:20:55 PM 300A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n mass index, heart rate, glucose and cholesterol levels. Fourteen volunteers (H-OSA- ;44±2 years), 15 hypertensives without OSA (H+OSA-;45±1 years), 15 normotensives with severe OSA (H-OSA+;44±2 years) and 14 hypertensives with severe OSA (H+OSA+;47±1 years) were submitted to carotid-femoral PWV analysis by non invasive device Complior®. Data were expressed as mean±SEM, and differences among groups were tested by ANOVA. Results: We observed signiﬁcant differences in sleep data, systolic blood pressure (SBP) and PWV according to the Table. H-OSA- (n=14) H+OSA- (n=15) H-OSA+ (n=15) H+OSA+ (n=14) AHI (events/hour) 3±0.3 3±0.5 55±6* 56±7* Minimal oxygen saturation (SatO2min) 90±0.6 90±0.5 74±2* 73±3* SBP (mmHg) 117±3 140±5†‡ 114±3 146±5§ PWV (m/s) 8.7±0.2 10.2±0.3|| 10.2±0.3|| 12.1±0.5#** * p<0.0001 vs H-OSA- and H+OSA-; † p=0.002 vs H-OSA-; ‡ p<0.0001 vs H-OSA+; § p<0.0001 vs H-OSA- and H-OSA+; || p=0.007 vs H-OSA-; # p<0.0001 vs H-OSA-; ** p=0.001 vs H+OSA- and H-OSA+ After adjustements for SBP, H-OSA+ group showed higher PWV values than H-OSA- (p<0.01). In addition, PWV values of H+OSA+ group remained signiﬁcantly higher than H+OSA- group (p=0.002). Conclusions: OSA impairs Arterial Stiffness in hypertensive patients providing potential additive effects of OSA in vascular changes induced by H. 915-212 Can An Assessment of Subjective Well Being Predict Outcomes in Patients with Hypertension and Coronary Artery Disease? A Report from the INternational VErapamil-SR/Trandolapril Study (INVEST) Eileen Handberg, Yan Gong, Rhonda Cooper DeHoff, L. Douglas Ried, Carl J. Pepine, University of Florida, Gainesville, FL Background: Quality of life (QOL) has been linked to compliance with medical therapy and outcome, but most validated QOL questionnaires are time consuming, require scoring, and are not practical for use in daily outpatient care. In this study we examined the relationship of a self reported estimate of subjective well being (SWB) from a 4 item choice and its relationship to adverse outcome in CAD patients with hypertension (HTN). Methods: The International VErapamil SR/Trandolapril STudy (INVEST) randomized 22,576 patients 50 years or older to a verapamil SR (Ve) or an atenolol (At) based strategy. After 61,000 patient-years follow-up, there were no differences comparing strategies with regard to BP control or the adverse outcome as ﬁrst occurrence of death, MI or stroke. At each visit patients rated their SWB over the previous 4 weeks as excellent (E), good (G), fair (F), or poor (P). Results: For all patients at baseline, SWB was excellent in 8.3%, good in 60.5%, fair in 28.7%, and poor in 2.7% with no differences by strategy (p = 0.83). There were 2269 patients who had an adverse outcome. For those patients who reported SWB as E at the visit prior to the outcome, 5.42% experienced adverse outcome, 8.39% of those reporting G, 15.35% reporting F and 35.89% reporting P (p < 0.0001). The odds ratio (95% CIs) for adverse outcome among those reporting SWB G (vs. E) was 1.52 (CI-1.26, 1.83), F 2.93 (CI 2.43, 3.56), and P 9.07 (CI 7.02, 11.73). When adjusted for strategy, age, gender, race, history of heart failure, prior MI, and BP control, the odds ratios (95% CIs) were similar, with those reporting SWB as G (vs. E) was 1.518 (1.25, 1.83); F was 2.74 (2.24, 3.35); P was 6.88 (5.24, 9.04). Conclusions: In CAD patients with HTN, self-reports of poor or fair SWB are signiﬁcant independent predictors of risk for near-term outcomes. This four item measure self report provides a simple, rapid tool to assess risk in these patients. 915-213 Alcohol-Associated Hypertension and Risk of Cardiovascular Hospitalizations Sheri Koplik, Erica Gunderson, Gary D. Friedman, Harald Kipp, Arthur L. Klatsky, Kaiser Permanente Medical Care Program, Oakland, CA BACKGROUND: Studies show an alcohol-hypertension (HTN) link, with HTN prevalence approximately doubled in heavy drinkers. Harmful and beneﬁcial effects of alcohol can confound study of long-term risks of HTN. To obviate this problem, we studied HTN sequelae separately in heavy drinkers, light drinkers & abstainers. METHODS: Among 127,212 persons with blood pressure (BP) and alcohol intake determined at 1978-85 examinations, we studied subsequent hospitalization risk at 5 alcohol-drinking strata (from never drinkers to 3+ drinks per day). With < 120/80 mmHg as referent, Cox proportional hazards models estimated relative risks (95% Conﬁdence Intervals) for JNC-VI BP categories; covariates were age, sex, race, BMI, education, and smoking. RESULTS: Selected data (table) show: (a) Increased risk is similar in heavy drinkers and abstainers with HTN for any cardiovascular (CV) condition, coronary disease, heart failure and stroke, (b) Heavy drinkers with HTN are more likely than abstainers with HTN to be hospitalized for the condition. Relations of “normal” BP (120-129/80-84 mmHg) &“high normal” BP (130-139/85-89 mmHg) BP were progressive for each condition, with similar patterns for alcohol drinking strata. CONCLUSION: Despite limitation by a single baseline alcohol and BP measure and inability to separate subjects with HTN due to alcohol from those with other causes of HTN, these data indicate that HTN among heavy drinkers carries risks at least as great as among light drinkers or abstainers . ADJUSTED RR (CI) OF HOSPITALIZATION FOR HTN (140/90+ mmHg) v OPTIMAL BP (<120/80 mmHg) Condition (ICD-9 code) N Abstainers 3+ drinks per day Any CV (390-459 18,962 1.9 (1.6-2.1) 1.8 (1.5-2.1) HTN (401-5) 1,086 3.1 (1.8-5.3) 6.7 (2.0-22.0) Coronary (410-4) 8,537 1.9 (1.6-2.3) 1.9 (1.4-2.4) Heart Failure (428) 3,374 2.9 (2.0-4.9 2.0 (1.2-2.8) Cerebrovascular (430-9) 5,309 2.1 (1.7-2.7) 2.0 (1.4-2.7 915-214 Inﬂuence of Blood Pressure Versus Overweight/Obesity on Biomarkers of Vascular Health in Postmenopausal Women Judith Hsia, Joseph A. DeVita, Sharon Mulvagh, Jannet Lewis, Maria Canossa Terris, Guangyang Han, Margaret Prescott, George Washington University, Washington, DC, Novartis Pharmaceuticals, East Hanover, NJ Background: The concurrence of weight gain and blood pressure elevation among middle-aged women has made it difﬁcult to attribute changes in atherosclerotic risk to one cause or the other during this life period. We hypothesized that overweight/obesity and hypertension separately affect markers of inﬂammation, hemostasis, oxidative stress and endothelium-dependent vasoreactivity. Methods: Three groups of postmenopausal women, aged 48-60y, were enrolled: Group A-BMI 26-41 kg/m2, systolic blood pressure (SBP) 130-149; Group B-BMI 26- 41, SBP<120; Group C-BMI<25, SBP<120. We excluded women with diabetes or high cholesterol, smokers and those taking postmenopausal estrogen, selective estrogen receptor modulators or antioxidant supplements. Results: Among normotensive women, those with elevated BMI had higher levels of C reactive protein (CRP), interleukin-6 (IL-6), urinary F2 isoprostanes, and decreased ﬂow- mediated dilatation (FMD) assessed by brachial artery ultrasound, compared with normal weight women (Table). Among overweight/obese women, those with hypertension had higher levels of F2 isoprostanes compared with normotensive women, but similar levels of CRP, IL-6, PAI-1 and FMD. Conclusion: In postmenopausal women, overweight/obesity is associated with systemic oxidative stress, inﬂammation and endothelial dysfunction. Hypertension is associated with a further increase in systemic oxidative stress potentially further increasing cardiovascular risk. Effect of Hypertension and overweight/obesity on markers of atherosclerotic risk Group A Overweight/obese Elevated BP (n=65) B Overweight/Obese Normal BP (n=37) C Normal weight Normal BP (n=35) BMI, kg/m2 32.0+3.8 29.2+3.2* 23.2+1.8**+++ Systolic BP, mm Hg 138+6 109+8** 105+8** Diastolic BP, mm Hg 86+5 71+6** 69+7** CRP, mg/dl 4.7+4.6 3.8+2.6 1.4+1.2**+++ IL-6, pg/ml 2.5+1.8 2.7+3.5 1.7+1.7*+ F2 isoprostanes, ng/mg creatinine 0.67+0.40 0.46+0.24* 0.31+0.18* ++ PAI-1, ng/ml 27.5+17.1 27.7+16.0 21.4+18.1 FMD, % 7.2+5.1 8.4+5.1 11.8+5.8**++ *p<.01, **p<.001 vs A; +p<.05, ++p<.01, +++p<.001 vs B POSTER SESSION 933 Endothelium and Atherogenesis Sunday, March 12, 2006, 1:30 p.m.-5:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 1:30 p.m.-2:30 p.m. 933-159 Thrombospondin-4 A387p Polymorphism Is not Associated With Markers of Vascular Function and Incidence of Myocardial Infarction Folkert W. Asselbergs, Jennifer K. Pai, Tobias Pischon, JoAnn E. Manson, Eric B. Rimm, Harvard School of Public Health, Boston, MA, Brigham and Women’s Hospital, Boston, MA Background: Thrombospondin-4 (TSP-4) is expressed by human endothelial and smooth muscle cells of the vascular wall and may impact smooth muscle cell proliferation and the adhesion of endothelial cells. We tested whether TSP-4 A387P polymorphism was related to myocardial infarction in US men and women. We further examined the association between this TSP-4 polymorphism and markers of vascular function. Methods and Results: We conducted a prospective nested case-control study within the Nurses’ Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). The distributions of genotypes were in Hardy-Weinberg equilibrium both in cases and controls. ACC_2006_8_VascularDisease.indd 300 1/4/06 5:20:55 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 301A Vascular D isease, H ypertension, and P revention The allele frequency of TSP-4 A387P was 22.6% in the male control group and 20.1% in the women control group. No signiﬁcant differences were found in wildtype, heterozygote and homozygous variant genotype frequencies between cases and controls in the HPFS (60.2% versus 59.5%, 35.2% versus 35.8%, 4.7% versus 4.7%) and NHS (59.5% versus 64.1%, 34.4% versus 31.6%, 6.1% versus 4.3%). No signiﬁcant association was found between the TSP-4 A387P polymorphism and incidence of myocardial infarction. Furthermore, no signiﬁcant differences were found in levels of E-selectin, soluble intercellular adhesion molecule 1, and soluble vascular cell adhesion molecule 1 between genotypes. Conclusions: TSP-4 A387P polymorphism is not associated with myocardial infarction and markers of vascular function in US men and women. Odds ratio for cardiovascular disease Cases/ controls endpoint OR (95% conﬁdence interval) Women Wildtype vs. heterozygote+variant Wildtype vs. Variant 247/486 162/332 Nonfatal MI or fatal CHD 1.23 (0.90-1.70) 1.46 (0.71-2.98) Men Wildtype vs. heterozygote+variant Wildtype vs. Variant 264/528 171/339 Nonfatal MI or fatal CHD 0.97 (0.72-1.32) 0.95(0.46-1.95) Men Wildtype vs. heterozygote+variant Wildtype vs. Variant 820/1649 550/1100 Any CHD 0.99 (0.84-1.18) 1.02 (0.68-1.51) 933-160 Lipopolysaccharide Induces CXCR6 Expression in Human Coronary Artery Smooth Muscle Cells in TLR4 Dependent Myd88-TIRAP-TRIF-TRAF6 Mediated ERK1/2 Activation Devang N. Patel, Steven R. Bailey, Srinivas Mummidi, Bysani Chandrasekar, University of Texas Health Science Center, San Antonio, TX Introduction: Infection and inﬂammation play a causal role in atherosclerosis. Bacterial lipopolysaccharide (LPS) activates endothelial cells, smooth muscle cells (SMC), and macrophages. It has previously been shown to induce CXCL16 expression in SMC. CXCL16 signals via CXC receptor 6 (CXCR6) and induces SMC proliferation and migration. While CXCR6 expression and localization has been demonstrated in human and animal models of atherosclerosis, the stimuli leading to its induction remain poorly deﬁned. Methods: Human coronary artery smooth muscle cells (hCASMC) were treated with puriﬁed LPS. CXCR6 mRNA expression was analyzed by Northern blotting, nuclear run- on assays, and Actinomycin D pulse experiments. CXCR6 protein levels were quantiﬁed by Western blotting and ﬂow cytometry. TLR2, TLR4, MyD88, TIRAP, TRIF and TRAF6 expression were targeted by siRNA and dominant negative (dn) expression vectors. ERK activation was analyzed using immunoprecipitated p44/42 kinase and Elk-1 as a substrate. PD98059 was used as an ERK inhibitor. Results: Low levels of CXCR6 mRNA were detected in hCASMC at basal conditions. Treatment with LPS increased CXCR6 expression (at least 2.5-fold; p<0.01) in a time dependent manner. Increased gene transcription and mRNA stability both contributed to CXCR6 upregulation. LPS increased CXCR6 protein levels and surface expression. Knockdown of TLR4, but not TLR2, abrogated LPS mediated CXCR6 expression. Furthermore, inducible CXCR6 expression was inhibited (at least 2.8-fold, p<0.05) when the Toll adapters MyD88, TIRAP, and TRIF were targeted by siRNA. Expression of dnTRAF6 attenuated LPS signaling. Treatment with LPS increased ERK1/2 activation (4.1-fold, p<0.001) in PD98059 dependent manner. Finally, knockdown of MyD88, TIRAP and TRIF, and inhibition of TRAF6 and ERK attenuated LPS-mediated upregulation in CXCR6 expression. Conclusions: LPS/TLR4 signaling upregulates CXCR6 expression in hCASMC in MyD88, TIRAP, TRIF, TRAF6 and ERK dependent manner. Since LPS induces both the ligand (CXCL16; shown previously) and the receptor (CXCR6; present study), these studies together demonstrate a positive autocrine role of CXCL16/CXCR6 axis in atherogenesis. 933-161 Association of High Molecular Weight Form of Adiponectin With Endothelial Function in Healthy Young Men Hideo Matsui, Yasuhiro Ogawa, Tomohiro Yoshida, Masayuki Torigoe, Yasushi Numaguchi, Kenji Okumura, Toyoaki Murohara, Nagoya University Graduate School of Medicine, Nagoya, Japan Background: Adiponectin is an adipocyte-derived, antiatherogenic protein that is present in serum as a trimer or hexamer of relatively low molecular weight (LMW) and a larger multimeric structure of high molecular weight (HMW). However, the biological activities of these isoforms are controversial. In this study, we examined the effect of these isoforms on endothelial function in healthy young men. Methods: One hundred healthy young men without overt cardiovascular disease (aged 30.4 ± 4.2 years) were enrolled in this study. We evaluated endothelial function estimated by ﬂow-mediated dilation (FMD) of brachial artery during reactive hyperemia, using high- resolution ultrasound. We also measured total and high molecular weight form (HMW) of adiponectin levels, using ELISAs, respectively. LMW adiponectin level was calculated as: total adiponectin level- HMW adiponectin level. Results: Both LMW and HMW adiponectin levels showed a signiﬁcant inverse correlation with BMI (r = -0.253, P = 0.012 and r = -0.227, P = 0.024; respectively). FMD was signiﬁcantly correlated with fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), malondialdehyde-modiﬁed LDL (one oxidized form of LDL), LDL particle size, and HMW adiponectin (r = 0.320, P = 0.001), but not LMW adiponectin (r = 0 .125, P = NS). By multivariate analysis, LDL particle size and HMW adiponectin were selected as independent factors capable of inﬂuencing FMD (R2 = 0.268). No variable determined nitroglycerin-induced endothelium-independent dilation in this study. Conclusions: These results suggest that even in young men, HMW adiponectin level predicts endothelial dysfunction before any overt vascular disease has occurred. HMW adiponectin may be more sensitive as a marker of endothelial dysfunction compared with LMW adiponectin. 933-162 Lipoprotein-Associated Phospholipase A2 T403C Genetic Polymorphism Is Associated With Coronary Endothelial Dysfunction Eric H. Yang, Gregory D. Novak, Joseph P. McConnell, Geralyn Pumper, Susan A. Lagerstedt, Amir Lerman, Mayo College of Medicine, Rochester, MN Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is involved in the metabolism of oxidized phospholipids and is a predictor of coronary heart disease. A polymorphism in the 5’ region (T403C) has been previously detected. Objectives: To determine the effects of the T403C Lp-PLA2 polymorphism on coronary artery endothelial function. Methods: Seventy-four patients with no signiﬁcant coronary artery disease (>30% stenosis) were studied. Endothelial function was assessed by the change in coronary blood ﬂow in response to intracoronary acetylcholine. Genotyping was performed with PCR and site speciﬁc probes. Results: The wild-type genotype (T/T) was present in 36 (49%) of the patients. Thirty patients (41%) were heterozygous (T/C), and 8 (11%) were homozygous for the mutation (C/C). The T403C polymorphism was associated with worse endothelial function (Figure). Compared to T/T patients, T/C and C/C patients had greater serum concentrations of Lp-PLA2 (234 ± 61 and 233 ± 56 versus 203 ± 61 ng/ml, p < 0.001) and LDL cholesterol (106 ± 30 and 129 ± 30 versus 96 ± 31 mg/dl, p < 0.001). C/C patients were also more likely than C/T and T/T patients to have hypertension (75 versus 41 and 47%, p < 0.001), diabetes (25 versus 12 and 11%, p <0.001) and a greater body mass index (31.4 ± 5.9 versus 27.2 ± 5.2 and 27.8 ± 5.2 kg/m2, p < 0.001). Conclusion: The T403C Lp-PLA2 polymorphism is associated with higher serum levels of Lp-PLA2 and coronary endothelial dysfunction. 933-163 Curcumin Protects TNF-α-Induced Inﬂammatory Responses via NF-κB Inhibition in Endothelial Cells Yong Sook Kim, Youngkeun Ahn, Moon Hwa Hong, Soo Yeon Joo, Jeong Ha Kim, Young Joon Hong, Kye Hun Kim, Il Suk Sohn, Hyung Wook Park, Ju Han Kim, Weon Kim, Myung Ho Jeong, Jeong Gwan Cho, Jong Chun Park, Jung Chaee Kang, Chonnam National University Hospital, Gwangju, South Korea Background: Curcumin, a yellow pigment of turmeric in curry with anti-inﬂammatory and anti-oxidation properties, is reported to interfere with NF-�B. NF-�B is a well known transcription factor responsible for inﬂammatory and extracellular stress responses. This study was designed to investigate the underlying pathway of anti-inﬂammatory action of curcumin on endothelial inﬂammation. Methods: Human umbilical vein endothelial cell (HUVEC) was stimulated with TNF-� (10 ng/ml) in the presence or absence of curcumin (10 µM). Intracellular level of reactive oxygen species (ROS), U937 monocyte adhesion, activation of signal transducer and activator of transcription (STAT)-3, and c-Jun N-terminal kinase (JNK) were examined. The expressions of intercellular adhesion molecule (ICAM)-1, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-8 were analyzed by RT-PCR, western blot, or ELISA. NF-�B activation was determined by immunocytochemistry using p65 antibody. Results: Immunocytochemical study revealed nuclear translocation of NF-�B p65 by TNF-� was inhibited signiﬁcantly by curcumin (10 µM) in HUVEC. Curcumin suppressed intracellular ROS level (62.7% of control, p=0.008) and U937 monocyte adhesion (99.8% of control, p=0.001) in TNF-α-stimulated HUVEC. Phosphorylations of JNK and STAT-3 in TNF-� stimulated HUVEC were also inhibited by curcumin pretreatment. The expressions of ICAM-1, MCP-1, and IL-8 were attenuated by curcumin at both transcription and translation level. On the other hand, NF-κB inhibitor BAY 11-7082 and STAT-3 inhibitor AG490 reduced the U937 monocyte adhesion as well as the expressions of ICAM-1 and MCP-1 at mRNA and protein levels in TNF-α-stimulated HUVEC. Conclusions: This is the ﬁrst report that curcumin modulates STAT-3 activity in human endothelium. Curcumin inhibited the NF-κB activation to control the pro-inﬂammatory response, with ACC_2006_8_VascularDisease.indd 301 1/4/06 5:20:56 PM 302A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n additional inhibition of ROS generation, JNK, and STAT-3 in endothelial cells. These results suggested that curcumin-diet may be beneﬁcial to the patients under vascular wall inﬂammation. 933-164 Systemic Hypoxia Without Ischemic Organ Damage can Mobilize Endothelial Progenitor Cells in Human Peripheral Blood by Increased Levels of VEGF, MCP-1 and SDF-1: A Novel Insight of Hypoxic Preconditioning Chang-Hwan Yoon, Jin Hur, Woo-Young Chung, Young-Bae Park, Yun-Shik Choi, Hyo- Soo Kim, Seoul National University Hospital, Seoul, South Korea, Aeromedical center, Namil, Chungbuk, South Korea Background: Hypoxic preconditioning or systemic hypoxia has been shown to exhibit cardioprotective effects on myocardium from ischemic or reperfusion injury. However, there is no evidence that systemic hypoxia without ischemic injury mobilizes endothelial progenitor cells (EPCs) in human for hypoxia-induced angiogenesis. In the present study, we investigated whether systemic hypoxia recruit EPCs into human peripheral blood. Methods and Results: Twelve healthy volunteers who were undergoing an aircrew training course experienced hypoxic hypoxia in the hypobaric chamber. Hypoxic hypoxia equal to the altitude of 15,000 feet (estimated PaO2: 45 mmHg, measured O2 saturation was 80±4%) was induced and maintained for 30 minutes. Blood samples were obtained at predetermined time points: pre-exposure, post-exposure 30 min, 3 hr, 6hr and 24hr. Levels of VEGF, IL-8, MCP-1, SDF-1, G-CSF and EPO were measured using ELISA to evaluate EPCs mobilizers in response to hypoxia. Number of EPCs (AC133+/CD14-, CD34/KDR double positive, VE-cadherin+) in the peripheral blood was quantiﬁed using ﬂow cytometry. We performed EPC culture and compared the size and number of the EPC colonies. We found that the levels of VEGF, MCP-1 and SDF-1 were increased 3 h after hypoxia exposure (VEGF: 276±150 to 431±176 pg/mL, p=0.01; MCP-1: 270±21 to 360±80 pg/mL, p=0.04; SDF-1: 25±19 to 160±76 pg/mL, p=0.007) and normalized at 24 h. IL-8, however, was decreased (32±29 to 17±21, p=0.02) whereas G-CSF and EPO were not changed (p>0.05). The number of AC133, KDR and CD34 positive cells was increased 3 h after hypoxia (AC133+ cells: 0.15±0.07 to 0.24±0.11%, p=0.001; KDR+/CD34+ cells: 0.05±0.04 to 0.19±0.12%, p=0.002) and then maintained for 24 h. In addition, the size and number of EPCs colonies were also increase after exposure to hypoxia (colony count: 10.8±5.7 at pre-exposure to 16.5±6.2 at 3 h, p<0.001). Conclusions:EPCs were acutely mobilized in the human peripheral blood after systemic hypoxia by increased levels of VEGF, MCP-1 and SDF-1. The mobilization of EPCs may be a physiologic response to hypoxia which possibly contributes to myocardial capillary angiogenesis and coronary ﬂow reserve for ischemia tolerance. 933-165 A Novel Method for Enumerating Circulating Endothelial Progenitor Cells Based on ALDH Activity Thomas J. Povsic, Katherine Lambeth, Francine L. Kelly, Enrikas Vainorious, Michael H. Sketch, Jr., Pascal J. Goldschmidt-Clermont, Eric D. Peterson, Duke Univeristy Medical Center, Durham, NC Background: Interest in the assessment of circulating endothelial progenitor cells (EPCs) is growing as evidence of their role in vascular repair mounts. Progenitor cells exhibit high levels of aldehyde dehydrogenase (ALDH) activity. The use of ALDH activity for enumerating EPCs has not been tested. We hypothesized that ALDH activity might form the basis for a more reliable and reproducible assay of EPCs then previously described methods. Methods: We determined EPCs based on level of ALDH activity and compared these to EPCs enumerated based on CD133/CD34 expression or cell culture techniques. The reproducibility and stability over time of EPCs enumerated by each assay was compared. The numbers of ALDH+ cells were compared with other measures of EPCs in a cohort of 198 patients undergoing cardiac catheterization. Results: The interassay variability of EPC counts determined using ALDH activity was lower than those determined using other assays. The numbers of ALDH+ cells correlated closely with CD133+/CD34+ cells (p<0.001); however, no correlation was observed with EPCs identiﬁed on the basis of culture techniques. ALDH+ and CD133+/CD34+ EPCs were correlated with extent of coronary disease, but correlation was higher with ALDH+ cells (* p<0.01 for pairwise comparison). Conclusions: ALDH activity is a novel method for identifying and quantitating EPCs in patients which is less variable than previously identiﬁed methods. The correlation of ALDH+ cells with clinical outcomes warrants further study. No CAD 1V CAD 2-3V CAD 0.00 0.05 0.10 0.15 p<0.001 for linear trendANOVA p<0.05 * * Extent of CAD AL DH br C el ls (% o f M NC ) 933-166 Usefulness of Membrane Type 1-matrix Metalloproteinase Measurement In Vivo as a Novel Indicator of Atherogenesis Hiroyasu Uzui, Akira Nakano, Naoki Amaya, Haruhisa Shirasaki, Toshihiro Mizuguchi, Junji Sakata, Michitomo Kawahito, Takanori Ueda, Jong-Dae Lee, University of Fukui, Fukui, Japan Background: Increase of active type matrix metalloproteinases (MMPs) is an important pathological step leading plaque vulnerability and Pericellularly localized membrane- type (MT)-MMPs are main activator of secreted latent type MMPs. However, MT- MMP expression in vivo is unclear in patients with ischemic heart diseases (IHD). We investigated the hypothesis that MT-MMPs are highly expressed on circulating peripheral blood mononuclear cells (PBMNCs) from patients with IHD. Methods: Serum and PBMNCs were prepared from fasting blood sample of patients with IHD (n = 61; Acute coronary syndrome (ACS), stable angina pectoris (SAP), old myocardial infarction (OMI)) and age matched control-subjects (Cont) (n = 15). PBMNCs were examined for the frequencies of CD14 positive cells expressing MT1-MMP at the single cell level using ﬂow cytometry. Serum levels of MMP-2,-9, TIMP-1,-2 were measured by using ELISA methods Results: (Table) Conclusions: MT1-MMP is highly expressed in patients with IHD, and these ﬁnding was observed in ACS especially. These ﬁnding suggested that the measurement of MT1- MMP on PBMNCs is repeatable methods in vivo, and may become a new indicator of atherogenesis and a predictor of ACS. 933-167 Toll-like Receptors in Giant Cell Arteritis: Differential Effects of TLR4 and TLR5 Ligation Wei Ma-Krupa, Stefan Groeschel, Kisha Piggott, Augusto Vaglio, Olga Pryshchep, Kazunori Shimada, Jorg J. Goronzy, Cornelia M. Weyand, Lowance Center for Human Immunology, Atlanta, GA, Emory University School of Medicine, Atlanta, GA Background: Giant cell arteritis (GCA) is a granulomatous vasculitis of medium-sized arteries, often affecting temporal arteries (TA). Activation of T cells and macrophages in the vasculitic inﬁltrates depends upon highly activated CD83+ dendritic cells (DC). Immature DC are present in healthy, non-inﬂamed TA, and their maturation can be initiated by Toll-like receptor (TLR) triggering. We have explored whether stimulation of TLR4 and TLR5 is sufﬁcient to induce vessel wall inﬂammation. Methods: Responsiveness of human non-inﬂamed TA to TLR4 or TLR5 ligation was tested in an organ culture system in which TAs are cultured with TLR ligands. Alternatively, human TAs were implanted into SCID mice followed by TLR ligand injection and adoptive transfer of CD4 T cells. DC activation was assessed by real-time PCR of CD83 and CCL19 transcripts and immunohistochemistry for CCL19 and CD83 protein. T-cell activation was determined by quantifying CD40L and IFN-� transcripts or measuring proliferation of T cells isolated from the arterial tissue. Results: Culturing of TAs with the TLR4 ligand LPS rapidly induced CD83 and CCL19 transcripts; immunohistochemistry revealed that CCL19 was exclusively derived from vascular DC. The TLR5 ligand ﬂagellin was equally potent in inducing CD83 but upregulated CCL19 production more effectively (P=0.012). To test whether this difference was biologically relevant, both ligands were compared in the chimera model. LPS injection resulted in activation of vascular DC and recruitment of CD4+ T cells into the artery graft. Adoptively transferred T cells underwent in situ activation and inﬁltrated into the media layer. Following ﬂagellin injection, DC in the implanted TA switched to a CD83+ phenotype and produced CCL19. Dense inﬁltrates of T cells accumulated in the arterial adventitia where they were stimulated to produce IFNγ. However, these T cells failed to invade the media. Conclusions: Stimulation by blood-borne LPS is sufﬁcient to induce activation of vessel wall DC, attraction and retention of T cells, and invasion into the tunica media. The bacterial product ﬂaggelin is superior in inducing T-cell recruitment, yet such T cells are arrested in the adventitia. 933-168 Deletion of Tumor Necrosis Factor α Receptor 1 Is Protective in A Mouse Model of Hindlimb Ischemia Jun Jiang, Changling Li, Jianan Wang, Shan Ping Yu, Ling Wei, Medical University of South Carlina, Charleston, SC, Sir Run Run Shaw Hospital, Hangzhou, People’s Republic of China Background: Signals in the tumor necrosis factor α (TNF α) pathway, including TNF � and tumor necrosis factor � receptor 1 (TNFR1), are upregulated after acute hindlimb ischemia. It is unclear, however, whether this upregulation is a pathophysiological consequence or a compensatory response. In the present study, we investigated the effect of TNFR1 deletion in a mouse model of hindlimb ischemia. Methods and Results: Hindlimb ischemia was induced through ligation of the proximal and distal left femoral artery and its branches in TNFR1 knockout (TNFR1-/-) and wild ACC_2006_8_VascularDisease.indd 302 1/4/06 5:20:56 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 303A Vascular D isease, H ypertension, and P revention type (WT) mice. Laser Doppler blood ﬂow measurement showed that limb perfusion was signiﬁcantly higher in TNFR1-/- mice than the WT mice 1 day after operation. The calculated ischemic scores were 3.67±0.52 in TNFR1-/- group and 1.83±0.41 in WT group (P < 0.05). The rate of amputation was 50% in WT mice versus 0% in TNFR1-/- mice. There were less TUNEL positive cells in the calf muscle of TNFR1-/- mice than that of WT mice. Furthermore, DNA laddering is more obvious in WT mice. Western blot showed less expression of Bax and cleaved caspase 3 in TNFR1-/- mice 1 day after ischemia, suggesting a reduced apoptotic process in the absence of TNFR1. Conclusions: In a mouse model of hindlimb ischemia, knockout of TNFR1 prevents the activation of death-related proteins down streaming to TNF α and attenuated cell death including apoptosis. Systemic block of the TNFR1 might be a new interventional strategy to preserve the limbs for acute ischemic attack in patients with peripheral arterial obstructive disease. 933-169 Therapeutic Angiogenesis Using Novel Vascular Endothelial Growth Factor-E / Human Placental Growth Factor Chimera Genes Natsuo Inoue, Takahisa Kondo, Yasushi Numaguchi, Toyoaki Murohara, Masabumi Shibuya, Nagoya University, Graduate School of Medicine, Nagoya, Japan Background: Vascular endothelial growth factor-A (VEGF-A) can promote angiogenesis but causes adverse side effects such as edema, atherosclerotic plaque development, or tissue inﬂammation. VEGF-E, which was found in the genome of the Orf virus, speciﬁcally binds to VEGF receptor-2. VEGF-E shows mitotic activity on endothelial cells via VEGFR- 2 activation. Unlike VEGF-A, VEGF-E does not increase vascular permeability and is not expected to induce edema. Recently, we created two forms of VEGF-E and human Placental Growth Factor (PlGF) chimera genes (VEGF-E/PlGF9 and VEGF-E/PlGF33), which are humanized genes holding VEGF-E function. Methods: We examined proangiogenic activities of these genes. Four types of plasmid (pCDNA3.1-βgal, phVEGF-A, pVEGF-E/PlGF9 and pVEGF-E/PlGF33, n=8 each) were administered in a rat hindlimb ischemia model. Results: pVEGF-E/PlGF9, pVEGF-E/PlGF33 and pVEGF-A signiﬁcantly increased ischemic/ normal hindlims laser doppler blood ﬂow (LDBF) compared with the control pCDNA3.1-βgal treated group (by 1.4 fold, 1.5fold, and 1.5fold respectively, p<0.05). Histochemical staining by alkaline phosphatase also revealed that pVEGF-E/PlGF9, pVEGF-E/PlGF33 and pVEGF-A treated groups had increased capillary density compared with the pCDNA3.1-βgal treated group(1.4 fold, 1.5fold and 1.5fold respectively, p<0.05). Furthermore, immunostaining for anti-ED1 revealed that lower number of macrophages were inﬁltrated in both pVEGF-E/ PlGF9 and pVEGF-E/PlGF33 groups compared with the pVEGF-A group. Conclusions: In conclusion, novel chimera genes, pVEGF-E/PlGF9 and pVEGF-E/ PlGF33, signiﬁcantly stimulated angiogenesis in response to tissue ischemia, whose extent was almost similar to that induced by phVEGF-A plasmid gene. Furthermore, VEGF-E chimera -mediated angiogenesis may avoid tissue inﬂammation often observed in VEGF-A-induced angiogenesis. 933-170 The Forkhead Transcription Factor, FOXO3a Controls Vascular Smooth Muscle Cells Proliferation through Modulation of an Angiogenic Immediate Early Gene, CYR61 Hae-Young Lee, Joo-Yong Hahn, Yong-Seok Kim, Jae-Jin Kwak, Kyung-Woo Park, Young-Bae Park, Byung-Hee Oh, Hyo-Soo Kim, Seoul National University Hospital, Seoul, South Korea Background: Cysteine-rich angiogenic protein 61 (CYR61) is an immediate early gene expressed in vascular smooth muscle cells (VSMCs) on growth factor stimulation and its expression has been associated with postangioplasty restenosis and atherosclerosis. The forkhead transcription factors are known to inhibit growth in a variety of cell types. We hypothesized that the forkhead transcription factor, FOXO3a, may play a role in regulating CYR61 expression in VSMCs. Methods and Results: 1) To evaluate FOXO3a effect on CYR61 expression, rat VSMCs were infected with adenoviral vectors expressing constitutively active FOXO3a (Ad-TM- FOXO3a). FOXO3a gene transduction suppressed CYR61 mRNA expression, which corresponded to decreased protein synthesis. 2) Transfection experiments with deletion constructs of the CYR61 promoter revealed the potential binding sites for forkhead transcription factor at the approximately 700-bp upstream of the TATA-box in promoter region. Co-transfection of Ad-TM-FOXO3a with the reporter plasmid (pGL3-CYR61) resulted in a signiﬁcant decrease in luciferase expression, conﬁrming CYR61 regulation by FOXO3a. 3) Ex vivo exposure of rat aortic rings to angiotensin II (10-9mol/L, 2 hours) rapidly induced CYR61 in VSMCs, which was signiﬁcantly reduced by Ad-TM-FOXO3a and recovered by antisense FOXO3a transduction. 4) In rat balloon carotid arterial injury model, CYR61 expressed in VSMCs in early stage of injury and remained elevated until 14 days, which was suppressed by Ad-TM- FOXO3a. After 14 days, there was a substantial reduction in neointimal area (0.20±0.07 versus 0.06±0.02mm², n=12, P<0.01) compared with the control group. This reduction in neointimal hyperplasia by FOXO3a was reversed by co-transfection of adenoviral vectors expressing CYR61 (Ad-CYR61). Conclusions: These data suggest that FOXO3a inhibits VSMC proliferation via downregulation of CYR61 and that this signaling axis may represent a therapeutic target in controlling atherosclerosis or vascular proliferative diseases. 933-171 Rapid Effects of 5-Methyl-Tetrahydrofolic Acid on Endothelial Function and Vascular Superoxide Production in Human Coronary Artery Disease Charalambos A. Antoniades, Cheerag Shirodaria, Paul Leeson, Justin Lee, Nicolas Warrick, Jennifer Bendall, David Taggart, Chandi Ratnatunga, Ravi Pillai, Keith M. Channon, University of Oxford, Oxford, United Kingdom Background: 5-methyltetrahydrofolic acid (5MTHF) may have antiatherogenic properties by reducing homocysteine, but its direct effects on vascular function are unclear. We evaluated the direct effect of 5MTHF on endothelial function, superoxide (SOO) production and intravascular levels of eNOS co-factor tetrahydrobiopterin (BH4), in human saphenous veins (HSV) and internal mammary arteries (IMA) of patients undergoing CABG. Methods: Vasomotor responses of HSV to acetylcholine (ACh) were evaluated ex-vivo in segments from 38 patients, before and after 45 min incubation with 5MTHF 0 or 1µM. Vascular SOO was measured by lucigenin chemiluminescence, in paired samples of HSV and IMA. Vascular biopterins were measured by HPLC. The direct SOO-scavenging capacity of 5MTHF was quantiﬁed using a xanthine/xanthine oxidase system. Results: 5MTHF improved the vasomotor responses to ACh (Fig a), and decreased SOO in both HSV and IMA (Fig b), an effect accompanied by an increase in both BH4 and BH4/ total biopterins ratio (Fig c). Whereas 5MTHF at high concentrations (100 and 1000µM) had direct SOO scavenging effect (-30±10% and -67±7% respectively, p<0.01 for both vs control), no direct scavenging was observed with concentrations ≤10µM. Conclusions: 5MTHF improves endothelial function and decreases SOO production in vessels from patients with CAD, by mechanism other that direct SOO scavenging. 5MTHF also increased vascular BH4, suggesting that it may exert its vascular effect by improving eNOS coupling. 933-172 Intraperitoneal Administration of Anti-Angio-Associated Migratory Cell Protein-Antibody Inhibits Neointima Formation After Vascular Injury in Apolipoprotein E Knockout Mice Felix Vogt, Alma Zernecke, Marie Beckner, Nicole Krott, Anja-Katrin Bosserhoff, Rainer Hoffmann, Christian Weber, Ruediger Blindt, University Hospital Aachen, Aachen, Germany, Pittsburgh University Medical Center, Pittsburgh, PA Background: Angio-associated migratory cell protein (AAMP) was described to participate in angio- and cancerogenesis and is predominantly expressed in cells with a migratory phenotype; thus, we investigated the contribution of AAMP to neointima (NI) development. Methods: Subcellular localization of AAMP in SMCs was examined using confocal scanning laser microscopy. AAMP contents of smooth muscle cells (SMCs) with different phenotypes were quantiﬁed by Western blot. Expression of AAMP was quantiﬁed in the apolipoprotein E knockout (apoE-/-) mouse model by immunohistochemistry and reproduced as AAMP-positive area of the neointima. Migratory potential of SMCs transiently transfected with AAMP sense expression vectors or treated with anti- recombinant AAMP (anti-rAAMP)-antibody was examined using Boyden chamber assays. ApoE-/- mice were treated intraperitoneally with anti-AAMP antibody, and NI area in wire- injured carotid arteries was quantiﬁed histomorphometrically after 4 weeks. Results: AAMP-transfected SMCs and SMCs of the migratory phenotype displayed intensiﬁed AAMP distribution along the ﬁlopodia. SMCs of the migratory phenotype displayed increased AAMP expression (34.9 ± 6.0 intensity/area) compared to the quiescent SMC phenotype (3.8 ± 0.3; P<0.01). Vascular injury enhanced AAMP expression in murine arteries after 1 week (92% AAMP-positive) and after 4 weeks (79%), as compared to non-injured control (49%; P<0.01). SMCs overexpressing AAMP displayed increased migratory potential (51.9 ± 4.1 cells/area), as compared to mock transfected cells (32.5 ± 2.3; P<0.01), and anti-rAAMP-antibody reduced migratory potential of medial (21.5 ± 4.0 cells/area) as well as neointimal (74.4 ± 11.6) SMCs compared to control (49.7 ± 3.8 or 164.5 ± 20.6; P<0.001). Anti-rAAMP-antibody reduced NI area development (42.1 ± 2.8 µm²) as compared to isotype control (78.7 ± 3.1; P<0.01) in wire-injured arteries. Conclusions: AAMP was upregulated in migratory and neointimal SMCs, AAMP overexpression led to increased migratory potential of SMCs, and blocking of AAMP reduced SMC migration and NI formation, thereby indicating a possible contribution of AAMP to NI formation. ACC_2006_8_VascularDisease.indd 303 1/4/06 5:20:58 PM 304A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n POSTER SESSION 934 Cell Therapy for Myocardial and Vascular Disease Sunday, March 12, 2006, 1:30 p.m.-5:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 1:30 p.m.-2:30 p.m. 934-173 Beneﬁcial Effect of Combined Intramyocardial and Intracoronary Administration of Autologous Stem Cells on Global and Regional Left Ventricular Function and Myocardial Perfusion in Patients With Ischaemic Cardiomyopathy Noemi Nyolczas, Mariann Gyongyosi, Gilbert Beran, Silvia Charwat, Irene Lang, Dietmar Glogar, Medical University of Vienna, Vienna, Austria Background: The aim of the present study was to assess the effect of combined (intramyocardial plus intracoronary) percutaneous administration of non-selected bone marrow-derived mononuclear cells treatment on global left ventricular ejection fraction (EF) and regional left ventricular wall motion, the extent of pharmacological stress- induced and rest perfusion defect in patients with ischemic cardiomyopathy, who are not amenable for conventional revascularization. Method: 17 patients (100% male, mean age: 62.1±11.8 years) with ischaemic cardiomyopathy under optimal medical trerapy have been treated with combined [NOGA-guided intramyocardial (3.97±0.69 ml) plus intracoronary (26.7±16.1 ml)] administration of autologous bone marrow-derived stem cells (total cell number: 1.11x109±1.32 x109; CD34+ cell number: 1.38x107±1.39 x107). Baseline and follow- up evaluation of myocardial viability and local wall motion abnormality by NOGA endocardial mapping; determination of size of resting and stress-induced perfusion defects by 99m-Tc-MIBI-adenosin-perfusion scintigraphy; measurement of global EF by contrast ventriculography and evaluation of wall motion score index by 2D echocardiography were performed in all patients. Results: The combined application form of the stem cell therapy induced signiﬁcant increase in global EF measured by contrast ventriculography (from 34.8±7.9 % to 39.5±6.7 %; p=0.015) as well as signiﬁcant increase in segmental wall motion measured by LLS with NOGA (from 5.14±2.90 % to 6.21±1.66 %; p=0.035) at the 6-month follow up. A trend to smaller stress-induced perfusion defects (from 37.0±10.3 % to 32.1±13.3 %; p=0.088) were documented at the FUP. The number of the total injected BM cells exhibited positive linear correlation with the FUP EF (p=0.01, r=0.709) and LLS (p<0.05, r=0.628), and negative linear correlation with the stress-induced (p=0.01, r=0.708) and resting (p<0.01, r=0.722) perfusion defects. Conclusion: In patients with ischaemic cardiomyopathy combined (intramyocardial and intracoronary) administration of autologous progenitor cells can improve global and regional left ventricular function and myocardial perfusion. 934-174 Vascular Dendritic Cells as Gatekeepers in Vascular Inﬂammation Kazunori Shimada, Wei Ma-Krupa, Tiffany L. Johnson, Robert M. Nerem, Jorg J. Goronzy, Cornelia M. Weyand, Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA Background: Intense vascular inﬂammation deﬁnes vasculitis, whereas smoldering inﬂammation is typical for atherosclerosis. The vessel wall provides a unique microenvironment for invading macrophages and T lymphocytes which function by interacting with tissue resident cells, such as dendritic cells (DC) and vascular smooth muscle cells (VSMC). To examine how DC and VSMC regulate lymphocyte recruitment, retention and wall invasion, we have bioengineered three-dimensional (3D) tubular constructs that mimic medium-sized human arteries. Methods: 3D tubes were constructed from human aortic VSMC and collagen type I matrix. For DC-reconstituted constructs, DC grown from CD14+ precursors were added to the distal media. Constructs were cultured with autologous CD4+ T cells for 36 hours. Cell activation and invasion were assessed by real-time PCR, immunohistochemistry, and computer-assisted microscopy of frozen sections. Results: DC-free tubular constructs attracted few CD4+ T cells. Even after pre-activating VSMC with LPS; such T cells failed to undergo activation. Similarly, only low frequencies of T cells attached to vessels reconstituted with immature DC. However, when DC- reconstituted constructs were stimulated with LPS, optimal conditions for T-cell attraction, retention, and invasion into the SMC layer were induced. Wall-embedded DC differentiated into CD83+ CD86+ DC (P=0.01) and produced the T cell-attracting chemokine CCL19. Such mature DC remained stationary in the distal media. Autologous CD4 T+ cells responded by accumulating at the outer media where they received activating signals and produced CD40L and IFN-γ. Approximately 10% of CD4+ T cells acquired a tissue- invasive phenotype and inﬁltrated deeply into the SMC layer (P=0.002). Conclusions: The early steps of T-cell activation and wall inﬁltration can be mimicked in bioengineered human blood vessels. Mature DC are required to attract, retain, and stimulate CD4+ T cells for their invasion into the SMC layer. Surprisingly, LPS triggering of wall-embedded DC breaks T-cell tolerance, suggesting a mechanism through which bacterial infections can increase the risk for vascular inﬂammation. 934-175 A Strategy of Retrograde Injection of Bone Marrow Mononuclear Cells Into the Myocardium for the Treatment of Ischemic Heart Disease Shin-Ichiro Yokoyama, Noboru Fukuda, Yuxin Li, Kazuhiro Hagikura, Taro Kawano, Tadateru Takayama, Junko Honye, Satoshi Saito, Hideo Mugishima, Nihon University School of Medicine, Tokyo, Japan Objective: Bone marrow cells implantation (BMI) is reported to efﬁciently improve ischemic heart disease. However, BMI strategies are generally invasive. To establish a BMI strategy for ischemic heart disease, we performed implantation of autologous cryopreserved mononuclear cells (MNCs) from bone marrow (BM) retrogradely into the myocardium via the coronary vein in pigs with acute myocardial infarction (AMI) and old myocardial infarction (OMI). Methods: BM cells were harvested from the pigs’ fumurs. MNCs were collected by centrifugation and were cryopreserved. Anterior myocardial infarction was induced by occlusion of the left anterior descending coronary artery. Frozen BM cells were quickly thawed and injected retrogradely via the coronary vein into the myocardium through a catheter 6 h and 2 weeks after the induction of infarction. Four weeks after implantation, coronary arteriograms were obtained, cardiac function was analyzed with the use of a conductance catheter, and histopathologic anlysis was performed with a confocal laser micropsope. Plasma levels of natriuretic peptides and angiogenic growth factors were measured after BMI. Results: Flow cytometric analysis revealed that ninety percent of cryopreserved BM cells were viable in vitro. Labeled BM cells were entirely distributed around in the infarcted area of maycardium. BMI increased collateral neovascuralization in infarcted hearts. BMI signiﬁcantly improved cardiac function in AMI with BMI and OMI with BMI groups. BMI also increased the formation of microcapillary arteries in infarcted hearts. Levels of natriuretic peptides were signiﬁcantly decreased, and levels of vascular endothelial growth factor and basic ﬁbroblast growth factor were signiﬁcantly increased after BMI. Confocal laser microscopy revealed the presence of proliferative and activated myocardial cells in infarcted hearts after BMI. Conclusion: The retrograde infusion of cryopreserved BM cells into myocardium efﬁciently induced angiogenesis and improved cardiac function in pigs with AMI or OMI. These results suggest that the present strategy of BMI will be safe and feasible as an angiogenic cell therapy for ischemic heart disease. 934-176 Transplantation of Autologous Endothelial Progenitor Cells is Safe, Feasible and Effective for Vascular Regeneration in No-Option Patients with Chronic Critical Limb Ischemia Atsuhiko Kawamoto, Minako Katayama, Nobuhiro Handa, Makoto Kinoshita, Haruna Takano, Rie Baba, Masanori Fukushima, Yasuki Kihara, Shigefumi Morioka, Takayuki Asahara, Kobe Institute of Biomedical Research & Innovation, Kobe, Japan, Kobe City General Hospital, Kobe, Japan Background: We have started a single-blind and dose-escalation clinical trial regarding transplantation of autologous CD34+ cells (known to be enriched for endothelial progenitors, EPCs) in patients with chronic critical limb ischemia (CLI). Methods: Patients with CLI by peripheral vascular disease or Buerger disease, in whom Rutherford class was 4-6 and who were not eligible for bypass surgery and angioplasty, were enrolled. Each patient underwent apheresis following 5-day subcutaneous administration of G-CSF (10 µg/kg/day). Peripheral blood CD34+ cells were isolated from the apheresis product by a magnetic cell sorting system and intramuscularly transplanted into a more severely ischemic leg of each patient under lumbar anesthesia. Cell dose for injection was 105 cells/ kg in initial 6 patients (Lo group: 4 male, 58±9 yrs) and 5 x 105 cells/ kg in next 6 cases (Hi group: 3 male, 40±5 yrs). Results: Safety and efﬁcacy was followed up to wk 12 after cell transplantation in both groups. No patients have experienced any severe adverse events such as death, MACE including myocardial/ cerebral infarction and major amputation. In all cases, Wong-Baker pain rating scale in the treated legs (PRS) was signiﬁcantly reduced by wk 4 (pre, 2.5±0.2; wk 4, 1.3±0.3, P=0.005) and further improved at wk 12 (0.8±0.3, P=0.0001). Toe brachial pressure index (TBPI), transcutaneous partial oxygen pressure (TcPO2) and pain-free walking distance by treadmill (PWD) had a tendency to improve at wk 4 and signiﬁcantly increased at wk 12 (TBPI: pre, 0.15±0.04; wk 4, 0.26±0.04; wk 12, 0.34±0.05, P=0.006 for pre vs wk 12) (TcPO2: pre, 10.2±3.4; wk 4, 24.5±6.5; wk 12, 41.4±5.7, P=0.003 for pre vs wk 12) (PWD: pre, 68.1±17.0; wk 4, 338.6±77.3; wk 12, 537.8±156.5, P=0.003 for pre vs wk 12). Although case number was small in each group, PRS, TBPI and TcPO2 were signiﬁcantly improved at wk 12 in Lo group, whereas TcPO2 and PWD were increased at week 12 in Hi group (P<0.05). Conclusion: Initial clinical experience suggests that mobilization, harvest and transplantation of autologous EPCs may be feasible, safe and effective in patients with CLI. Based on the current outcome, randomized and controlled trials for the cell therapy will be warranted. 934-177 Prolonged Adenovirus and Adeno-associated Virus- mediated Gene Delivery to Rabbit Iliac Arteries Using Gene-Eluting Stents: A Direct Comparison Faisal Sharif, Sean O. Hynes, Jillian McMahon, James Crowley, Timothy O’Brien, Regenerative Medicine Institute, NCBES, NUI Galway, Galway, Ireland Background: Gene- eluting stents are now being evaluated in animals as an alternative approach to inhibit in-stent restenosis. AAV and particularly adenovirus are commonly used for gene transfer applications. However, it is unknown whether these vectors can be eluted from a stent over a prolonged period. We tested the hypothesis that these vectors can achieve a prolonged and localized gene delivery to vessel wall using stents as delivery platforms. Methods: AdβGal and AAV2βGal at a concentration of 5 x 109 pfu and 5.3 x 109 drp respectively were used to coat BiodivYsio Hi ACC_2006_8_VascularDisease.indd 304 1/4/06 5:20:58 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 305A Vascular D isease, H ypertension, and P revention Matrix stents. Gene transfer was assessed at ﬁve time points (3, 7, 14, 21 & 28 days) using X-gal staining. After balloon injury, 3.0/11 mm stents were deployed in the external iliac arteries of NZW rabbits. 21 stents were used in the adenovirus group and 23 stents were used in the AAV group. Eight PC coated stents were used as controls. RT-PCR was used to assess distal spread of virus in multiple organs (n=6). Results: Expression of LacZ was demonstrated with both vectors at all time points. In the adenovirus group mean percentage of cells expressing transgene at 3 days was 5.15% which increased gradually to a mean expression of 9.85% at 28 days. Expression was localized to medial cells at day 3, but it was predominantly seen in neointimal cells at day 28. In the AAV group day 3 expression was 8.45% which gradually decreased to 1.73% at day 28(p<0.05). Gene transfer was also conﬁrmed in both groups using histological sections. No systemic dissemination of virus was seen in any group. Conclusions: Adenovirus and AAV2-coated stents can be used to deliver genes for up to 28 days. Expression was seen in the medial and neointimal cells. These vectors can be used to target the blood vessel wall in order to reduce the incidence of in- stent restenosis. 934-178 Adenoviral Fibroblast Growth Factor-4 Gene Therapy in patients With Stable Angina. 12-Month Results of a Double Blind Randomized Multicenter Trial G. Barbeau, K. Beatt, A. Betriu, S. Janssens, M. Martinez-Rios, B. Mautner, T. O’Brien, P. Paldanius, W. Ruzyllo, P. Smits, C. Sylven, S. Yla-Herttuala, B. Annex, P. Schoﬁeld, Steering Commitee Members for AGENT 4-study investigators, Berlin, Germany BACKGROUND: The primary objective of this study was to evaluate the effect of an adenoviral gene encoding ﬁbroblast growth factor (Ad5FGF-4) on exercise tolerance after 12 weeks and the overall safety of Ad5FGF-4 in patients with stable angina. The secondary objective was to evaluate the effects of Ad5FGF-4 on all-cause mortality and non-fatal coronary events up to 1 year. Recruitment of 450 planned patients to the study was prematurely terminated due to the observation of futility of the primary efﬁcacy endpoint in a sister study with similar design and therefore some of the pre-deﬁned analyses could not be performed. METHODS: We randomized 116 patients in a multinational, multicenter double blind study to one of three groups receiving a single intracoronary injection of two doses, 10E9 (low dose) and 10E10 (high dose) viral particles, of Ad5FGF-4 or placebo. RESULTS: No relevant tolerability or safety issues were identiﬁed. Transient fever and < 2 times increase in liver enzymes in six patients in the active groups were observed but the events were not unexpected for this patient population. No viral shedding was detected (from 6 hours to 7 days post-injection) and no circulating FGF-4 (from 18 hours to 8 weeks). The differences between the changes in the treadmill exercise duration (53, 54 and 58 seconds for placebo, low and high dose, respectively) and the proportion of patients whose treadmill exercise duration increased from baseline by >30% (co-primary endpoint) at Week 12 showed no statistical signiﬁcance between the three different treatment groups. The secondary efﬁcacy endpoint, the effects of Ad5FGF-4 on all-cause mortality and coronary events up to 1 year, showed a total of 21 adjudicated coronary events. By excluding six procedure-related events there were fewer events in the active treatment groups: 8 (placebo), 4 (low dose) and 3 (high dose). Improvements observed in all treatment groups in primary and tertiary efﬁcacy variables were associated with a substantial placebo response. CONCLUSIONS: Intracoronary injection of Ad5FGF-4 in tested doses appeared safe and well tolerated in patients with stable angina. A substantial placebo response was observed for the efﬁcacy parameters. POSTER SESSION 935 Risk Factors for Vascular Disease Sunday, March 12, 2006, 1:30 p.m.-5:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 1:30 p.m.-2:30 p.m. 935-179 Evolution in Stroke Risk Factors and Medications Over 20-Year Population-based Stroke Registry Isabelle Benatru, Jerome Durier, Olivier Rouaud, Pierre Sicard, Marianne Zeller, Yves Cottin, Jean-Bernard Henrotin, Guy-Victor Osseby, Maurice Giroud, Stroke registry of Dijon, Dijon, France, Service de cardiologie CHU, Dijon, France Background: We ascertained changes in risk factors and use of primary preventive treatments and their impact on incidence, and handicap rate at 1 month (Rankin score) of ﬁrst-ever stroke from a continuous 20-year well-deﬁned population-based study. Methods: From 1st january 1985 to 31st december 2004, 1 920 ischaemic strokes from large artery atheroma, 725 from small perforating artery atheroma, 497 cardio-embolism, 341 primary cerebral hemorrhage, 74 subarachnoïd hemorrhage and 134 undetermined ischaemic strokes were included in the registry. Results: The mean age signiﬁcantly increased from 1985 to 2004 (66.0 vs 71.1 in men, p = 0.009 ; 67.8 vs 75.6 in women, p = 0.002) as well as the absolute number of stroke (875 to 972). Hypercholesterolemia and diabetes increased (11.7 % vs 28.7 %, p < 0.0001 and 10.4 % vs 17.5 %, p < 0.0001 respectively). In contrast, smoking, DBP ≥ 90 mmHg and previous myocardial infarction decreased (37.8 % vs 25.2 %, p < 0.0001 ; 53.7 % vs 36.4 %, p < 0.001 ; 22.2 % vs 17.9 %, p = 0.015 respectively), hypertension (65.3 % vs 64.1 %, p = 0.57), previous transient ischemic attacks (25.2 % vs 22.3 %, p = 0.12) and previous atrial ﬁbrillation (22.9 % vs 23.1 %, p = 0.91) remained stable. Anti-platelet and anticoagulant therapy increased (5.2 % to 27.2 %, p < 0.0001 ; 2.6 % to 7.7 %, p < 0.0001 respectively) whereas hypertension treatment remained stable (47.9 % vs 49.0 %, p = 0.62). Age- and sex-adjusted incidences of ﬁrst-ever stroke were stable over time except for lacunar strokes whose incidence increased (p = 0.005), whereas cardio- embolic incidence decreased (p = 0.002). Minor handicap signiﬁcantly increased (p = 0.003) associated with a signiﬁcant fall in severe handicap (p = 0.001). Conclusions: Over the past 20 years, the medical practice improved with a signiﬁcant rise in antiplatelet and anticoagulant stroke-preventive therapy. However, we noted an absence of decrease in global stroke incidence, and a redistribution of incidence rates among the stroke sub-types associated with vascular risk factors evolution. This is the ﬁrst study of this magnitude showing that major risk factors for stroke remain uncompletly controlled and may explain the absence of decrease of stroke incidence. 935-180 Even Mild Reductions in Baseline Hemoglobin Concentration Increase the Risk of Death Among Cardiovascular Patients With Normal Ejection Fraction and no History of Myocardial Infarction Tami L. Bair, Donald L. Lappé, Brianna S. Ronnow, John F. Carlquist, Dale G. Renlund, Robert R. Pearson, Kurt R. Jensen, Benjamin D. Horne, Joseph B. Muhlestein, LDS Hospital, Salt Lake City, UT, University of Utah, Salt Lake City, UT Background: Anemia has long been associated with many forms of chronic disease. Recent studies have indicated that even moderate levels of anemia can be detrimental. It has been reported that anemia is a risk factor for patients with acute myocardial infarction (MI) and those with heart failure (HF); however, it is unknown whether the risk to cardiovascular (CV) patients is limited to those diagnoses. We sought to evaluate the effect of baseline hemoglobin (HGB) values in CV patients with a normal left ventricular ejection fraction (EF) and no history of MI. Methods: A population of 9,379 CV patients undergoing coronary arteriography with an EF >50%, no history of MI, and a baseline HGB was evaluated. Patients were followed for an average of 5.2 years for the outcome of all-cause mortality. Using quartiles, patients were divided into 4 HGB groups. The groups included patients with HGB levels ≤ 13.3 g/dL = Q1 (n=2226), 13.4-14.5 g/dL = Q2 (n=2262), 14.6-15.5 g/dL = Q3 (n=2219), and ≥15.6 g/dL = Q4 (n=2269). Results: Average age was 63±13 years, 61% were male, 18% were diabetic, 63% had severe [≥1 major coronary artery ≥70% stenosed] CAD and 1% had renal failure (serum creatinine >2.0 mg/dL). Overall, 16.9% died. Univariate analysis showed higher risk of death for the 3 lower HGB groups compared to Q4 (Q1: HR=3.43 [95% CI=2.94-4.00], p<0.0001; Q2: HR=1.61 [95% CI=1.36-1.91], p<0.0001; Q3: HR=1.20 [95% CI=1.01-1.44], p=0.038). After adjustment for 7 traditional CV risk factors and CAD severity, the effect remained for Q1 and Q2 (Q1: HR=2.49 [95% CI=2.10-2.95], p<0.0001; Q2: HR=1.35 [95% CI=1.13-1.60], p=0.001; Q3: HR=1.08 [95% CI=0.90-1.29], p=0.407). Conclusions: This observational study of 9,379 CV patients demonstrates that even mild (<14.5 mg/dL) reductions in baseline HGB levels are independently associated with future death even in patients with normal EF and no history of MI. The risk is markedly increased for more severe (HGB<13.3 mg/dL) levels of anemia. Whether directly addressing anemia in this population will improve outcomes will require further testing. 935-181 Cumulative Adverse Effects of Upper Respiratory Tract Infections on Carotid Artery Elasticity in Children With Type 1 Diabetes Mellitus Petru Liuba, Michal Odermarsky, Pesonen E, Annica Maxedius, Michal Odermar, E. Pesonen, Annica Maxedius, Pediatric Cardiology, Lund, Sweden Background: Infection has been hypothesized to contribute to the development of atherosclerosis particularly in conjunction with other cardiovascular risk factors. Data from several experimental animal studies have suggested possible cumulative adverse effects of repeated infections on arterial wall. Viral infections in the upper airways are more common in diabetic patients as a consequence of impaired immunity. Methods: Common carotid artery compliance (CAC), stiffness index (SI) and intima- media thickness (IMT) were assessed by high-resolution ultrasound (13-MHz linear-array transducer connected to Siemens Sequoia 512) in 51 children (mean age: 14.7±0.4 y) with type 1 diabetes mellitus recruited from the outpatient clinic of Children’s Hospital Lund. Upon the ultrasound visit, children and their guardians were asked about the number of viral upper respiratory tract infections (URTI) experienced during the past 12 months. Plasma CRP, orosomucoid and HbA1C were also measured. Data are mean ± SEM. CAC=([Ds-Dd]/Dd)/(Ps-Pd); SI= ln(Ps/Pd)/([Ds-Dd]/Dd). Results: CAC was decreased in those children with high prevalence (more than 4 per year; n=18) of URTI as compared to the remaining children (2.4±0.2 vs 3.1±0.3 %/10 mmHg, respectively; p=0.06). Similarly, SI was increased in children with frequent URTI (more than 4 per year) as compared to the remaining children (2.5±0.07 vs 2.7±0.08 respectively; p=0.09). No difference (p>0.2) was noted in IMT, age, diabetes duration, HbA1C, and inﬂammatory indexes (CRP and orosomucoid) between these 2 groups. Conclusion: Recurrent viral infections in the upper airways seem to have cumulative deleterious effects on the arterial elasticity in diabetic children. Further prospective studies are needed to verify whether these changes might in time translate into adverse effects on arterial structure. The study was funded by the Flight Attendant Medical Research Institute (PL). 935-182 The Association Between Coffee Consumption and Inﬂammatory Markers, in Healthy Individuals: The ATTICA Study Christina A. Chrysohoou, Demosthenes B. Panagiotakos, Christos E. Pitsavos, Christodoulos I. Stefanadis, First Cardiology Clinic University of Athens, Athens, Greece, Harokopio University, Athens, Greece Background: The effect of coffee consumption on the cardiovascular system is conﬂicting. Inﬂammation plays an important role in the development of cardiovascular ACC_2006_8_VascularDisease.indd 305 1/4/06 5:20:58 PM 306A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n disease (CVD), while several dietary factors are thought to exert signiﬁcant effects on inﬂammation and subsequently inﬂuence risk of CVD.the purpose of this study is to investigate the associations between coffee consumption and inﬂammatory markers. Methods: Cross-sectional survey enrolling 1514 men (18-87 years old) and 1528 women (18-89 years old). 5% of men and 3% of women were excluded due to history of CVD. Fasting blood samples were collected. Dietary habits (including various types of coffee consumption) were evaluated using a validated food frequency questionnaire. Results: Compared to non-coffee drinkers men who consumed > 200 ml/d had 50% higher interleukin (IL)-6 (p < 0.05), 30% higher C-reactive protein (CRP) (p < 0.05), 12% higher serum amyloid - A (SAA) levels (p < 0.05), 28% higher tumor necrosis factor (TNF)-a (p < 0.05) and 3% higher white blood cell counts (WBC) (p < 0.05). Women who consumed > 200 ml/d had 54% higher IL-6 (p < 0.05), 38% higher CRP (p < 0.05), 28% higher SAA levels (p < 0.05), 28% higher TNF-a (p < 0.05) and 4% higher WBC counts (p < 0.05), as compared to non-coffee drinkers. The ﬁndings were signiﬁcant even after controlling for the interactions between coffee consumption with age, sex, smoking, body mass index, physical activity status and other covariates. Conclusions: A relationship exists between moderate to high coffee consumption and increased inﬂammation process and may explain, in part, the effect of increased coffee intake on the cardiovascular system. 935-183 Oxidative Stress Is a Mechanism Underlying the Obesity Related Risk of Atherosclerosis in Healthy Adults Salman Ashfaq, Dean P. Jones, Syed Rafﬁ, Steven D. Rhodes, Faiz Cheema, Jerome L. Abramson, Viola Vaccarino, W. Craig Hopper, William S. Weintraub, David G. Harrison, Arshed A. Quyyumi, University of Kansas-School of Medicine, Wichita, KS, Emory University, Atlanta, GA Background: Increased risk of atherosclerosis in obesity is often attributed to associated dyslipidemia, insulin resistance, and inﬂammation. We hypothesized that oxidative stress is a mechanism underlying the increased risk of atherosclerosis associated with obesity. Methods: We studied 120 healthy non-smoking adults aged 30-65 years with no clinical atherosclerosis. Obesity was deﬁned as BMI > 30. To detect early atherosclerosis, ultrasound measurement of carotid intima-media thickness (IMT) was obtained. Inﬂammation was assessed by measuring C-reactive protein (hs-CRP). Oxidative stress was estimated by measurement of the redox state of plasma glutathione pool (Eh GSH/ GSSG), an important antioxidant system. Results: In addition to other traditional risk factors, elevated BMI, hs-CRP, fasting insulin, and Eh GSH/GSSG were all univariate predictors of IMT. Compared to non- obese individuals, obese subjects had higher hs-CRP level (2.1±3.8 vs. 7.2±7.6 mg/L, p<0.0001), elevated fasting insulin (4.8±3.1 vs. 8.8±4.2 U/ml, p <0.0001), and more oxidized Eh GSH/GSSG (- 127.2±7 vs. - 123.7±8 mV, p=0.046). After multiple linear regression analysis to adjust for traditional risk factors, fasting insulin, and hs-CRP, elevated BMI still independently predicted higher IMT (beta=0.21, p=0.02). Thus, after adding the oxidative stress marker, Eh GSH/GSSG, to the multivariate analysis, BMI no longer independently predicted IMT. Conclusions: In addition to dyslipidemia, insulin resistance, and inﬂammation, the obesity related risk of carotid wall thickening in otherwise healthy adults appears to be related to oxidative stress measured by the glutathione redox state. Elevated oxidative stress may be an additional pro-atherogenic pathway in obese subjects. 935-184 The Relationship Between soluble-Intercellular Adhesion Molecule - 1 and Race/Ethnicity Michelle A. Albert, Robert J. Glynn, Julie Buring, Paul M. Ridker, Brigham and Women’s Hospital, Boston, MA, Harvard Medical School, Boston, MA Background: Plasma levels of soluble intercellular adhesion molecule-1 (ICAM-1) are elevated in persons at risk for future cardiovascular events. In the United States, while vascular morbidity and mortality vary by race/ethnicity, data assessing the relationship between this inﬂammatory marker of vascular risk and race/ethnicity are limited. Methods and Results: ICAM-1 levels were measured at baseline among 23,687 women without a history of cardiovascular disease (CVD) participating in the Women’s Health Study. Among 22,677 white, 242 Hispanic, 428 black and 340 Asian women, median ICAM-1 levels were signiﬁcantly lower among black (311.9 ng/ml, interquartile range (IQR) 220.1 - 380.0) and Asian (312.7 ng/ml, IQR 267.3 - 362.3) women than among white (343.1, IQR 301.9 - 394.9) and Hispanic (351.9 ng/ml, IQR 305.9 - 404.2) women (p value < 0.001). This pattern is different from that previously observed in this cohort for C-reactive protein (CRP). ICAM-1 levels were higher among women not taking hormone replacement therapy (HRT). Overall, there were modest correlations between ICAM-1 levels and smoking (r= 0.29), body mass index (r=0.22), high-density lipoprotein (r= - 0.22), triglyceride level (r=0.24), Apo B to A1 ratio (r=0.25) and CRP (r=0.29) [all p <0.05]. In multivariate analyses, a history of current smoking and black race were the strongest predictors of s-ICAM-1 levels. In a model that controlled for body mass index, hypertension, diabetes, smoking status, alcohol use, family history of myocardial infarction, education level, hormone use and lipid parameters, ICAM-1 concentrations continued to remain signiﬁcantly lower among black and Asian women than their counterparts. Conclusion: Among apparently healthy women, ICAM-1 levels vary by self-reported race/ethnicity in a pattern different from that of CRP. 935-185 High Level of Fibrinogen is Associated with Occlusive Coronary Artery Spasm Weon Kim, Myung Ho Jeong, Young Keun Ahn, Young Joon Hong, Kye Hun Kim, Il Suk Sohn, Ju Han Kim, Hyung Wook Park, Jeong Gwan Cho, Jong Chun Park, Jung Chaee Kang, Chonnam National University Hospital, Gwangju, South Korea Background: Although elevated serum ﬁbrinogen and lipoprotein (a) [Lp(a)] are known to be associated with coronary atherosclerosis and AMI with thrombus formation, the association between the elevated level of ﬁbrinogen or Lp(a) and coronary spasm remains to be elucidated. The purpose of this study is to determine whether the elevation of serum ﬁbrinogen, Lp(a) levels is a risk factor for coronary spasm and also for the development of AMI in patients with coronary spasm. Methods: Consecutive 231 patients documented coronary vasospasm by ergonovine provocation test were divided two groups, angina pectoris (group I; n=202, 49.5±11.1 years) and acute myocardial infarction (group II; n=29, 47.4±11.2 years). Results: Baseline clinical characteristics were not different between the two groups. The serum Lp(a), ﬁbrinogen, hsCRP, apolipoprotein A1/B ratio were measured. The levels of Lp(a), hsCRP, ﬁbrinogen were higher (respectively, p<0.029, p<0.002, p<0.000) in group II (29.6±24.8 mg/dl, 1.88±2.9 mg/dl, 317.5±51.2 mg/dl) than in group I (21.2±17.8 mg/ dl, 0.68±1.5 mg/dl, 263.2±70.3mg/dl), but Apo(A1/B) level was lower in group II than in group I (0.66±0.21 vs. 0.87±0.37, p<0.03)). Multivariate analysis demonstrated that higher ﬁbrinogen level is only independent determinant for AMI (odds ratio=8.35; 95% CI=1.94 to 30.0). Conclusions: Elevated level of ﬁbrinogen is associated with AMI in patients with coronary spasm, suggesting that ﬁbrinogen may play an important role in the genesis of thrombotic coronary occlusion subsequent to coronary spasm. POSTER SESSION 936 Pulmonary Arterial Circulation Sunday, March 12, 2006, 1:30 p.m.-5:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 1:30 p.m.-2:30 p.m. 936-186 Peak Systolic Strain and Strain Rate in Children With Pulmonary Hypertension: A Tissue Doppler Study and Correlation With Cardiac Catheterization Data Karrie L. Dyer, Linda B. Pauliks, Elizabeth M. Shaffer, D. Dunbar Ivy, Lilliam Valdes-Cruz, University of Colorado, and the The Children’s Hospital, Denver, CO, New England Medical Center, and theTufts, Boston, MA Background: We hypothesized that chronic right-ventricular (RV) pressure overload in pulmonary hypertension (PH) leads to progressive RV dysfunction. However, in the early stages, the changes might be to subtle for detection by standard, qualitative assessment of RV function on 2D echocardiogram. Tissue Doppler strain imaging now offers a quantitative method to assess RV wall motion and has been validated against invasive reference standards of RV function and MRI in experimental studies and in adults. This study therefore tested RV strain (�) and strain rate (SR) in children with PH conﬁrmed by cardiac catheterization and a normal age-matched control group. Methods: Color tissue Doppler images were recorded in 14 children (age 9.5± 7.3y) with PH (mean pulmonary artery pressure 52±23mmHg by invasive measurement) and 26 controls (10.2±4.7y, NS) using high frame rates (>100/s). Off-line analysis was used to compare tricuspid ring peak systolic (S) velocities to peak systolic SR and � in the mid RV free wall. Results: All PH patients had lower S velocities, SR and � than controls (table). SR did not correlate with age or heart rate but velocities did. Conclusions: The diminished RV velocities, � and SR in the children with PH point to RV dysfunction even in those PH patients without overt signs of right heart failure. RV peak systolic SR may be the best marker for the pediatric age group since it is less age-dependent than tricuspid ring velocities and, based on experimental data, also may be less load-dependent than ε. RV Strain and Strain Rate in Pulmonary Hypertension Color Tissue Doppler Marker Control (n=26) PH (n=14) P value S velocity (cm/s) 10.0 ± 1.7 6.8 ± 2.0 p < 0.05 Strain (%) -30.8 ± 7.1 -20. 4 ± 5.1 p< 0.05 Strain Rate (1/s) -2.8 ± 0.9 -1.9 ± 0.6 p< 0.05 936-187 Characterisation of the Vasodilatory Action of Testosterone in the Human Pulmonary Circulation Alyson M. Smith, Robert T. Bennett, T. Hugh Jones, Mike E. Cowen, Kevin S. Channer, Richard D. Jones, Royal Hallamshire Hospital, Shefﬁeld, United Kingdom, Castel Hill Hospital, Hull, United Kingdom Background: This study was carried out to assess for the ﬁrst time, the vasodilatory effect of testosterone in the human pulmonary circulation. The inﬂuence of gender upon the response to testosterone was also studied. Methods: Isolated human pulmonary arteries were studied by wire myography. Vessels were obtained from male (n=7) and female (n=6) patients. Vessels were preconstricted with U46619 (1µM) prior to exposing them to either testosterone or ethanol vehicle. Isolated lungs were studied in a ventilated and perfused model (methodology described in [Bennett et al 2004]). Lung samples (n=12) were obtained from male (n=6) and female (n=6) patients. They were exposed to potassium chloride (KCl) (100mM), prior to the addition of either testosterone (1nM-100µM) or ethanol vehicle. Results: In the isolated human pulmonary arteries, testosterone caused signiﬁcant vasodilatation compared to ethanol vehicle (Table 1). Results from the isolated perfused human lung model showed greater responses to testosterone than the isolated pulmonary arteries (Table 1). There was however no signiﬁcant difference in the magnitude of the response to testosterone dependant upon gender (Table 1). ACC_2006_8_VascularDisease.indd 306 1/4/06 5:20:59 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 307A Vascular D isease, H ypertension, and P revention Conclusions: Testosterone acts as an efﬁcacious vasodilator in the human pulmonary circulation, with no marked differences observed in the response dependant on sex. Testosterone may therefore be a potential novel agent in the treatment of pulmonary vascular disease, namely pulmonary hypertension. % relaxation (SEM),*=signiﬁcant dilation compared to ethanol, p<0.05 via student t test Experiment details 1µM Testosterone 3µM Testosterone 10µM Testosterone 30µM Testosterone 100µM Testosterone Male pulmonary artery -0.3 (±1.0) -0.3 (±1.2) -1.4 (±1.3) -4.4 (±1.9) * -20.5 (±3.5) * Female pulmonary artery -4.4 (±4.1) -4.4 (±4.8) -4.7 (±4.7) -7.4 (±4.3) -27.9 (±4.3) * Male isolated perfused lung -15.0 (±20.2) -25.0 (±24.9) -28.4 (±23.7) * -51.0 (±23.3) * -106.5 (±18.3) * Female isolated perfused lung -3.2 (±6.1) -6.1 (±3.2) -22.6 (±8.7) -47.7 (±10.8) * -101.3 (±10.1) * 936-188 Resveratrol Induced Up-Regulation of Vascular Endothelial Growth Factor in Monocrotaline-Induced Pulmonary Hypertension Dongseok Lee, Sungmin Choi, Dookwon Kim, Yongwook Jung, Dongguk University Hospital, Kyungju, South Korea Background:: Resveratrol, a natural polyphenolic phytoalexin, in red wine has been demonstrated to be capable of protecting against cardiovascular disease because of its antioxidant and anti-inﬂammatory effects. We investigated whether resveratrol might protects monocrotaline (MCT) - induced pulmonary hypertension and whether vascular endothelial growth factor (VEGF) is involved in the beneﬁcial effects. Methods: Male Sprague Dawley rats were injected with distillated water (Control, n = 6) or monocrotaline (MCT; 60 mg/kg). Subsets of MCT animals (n = 8 per group) received either 5 mg/kg/day of resveratrol or placebo. After 28 days, morphometric analysis and expression of VEGF in lung with MCT and/or resveratrol were determined by the immunohistochemistry and Western blot. Results: In the MCT group, right ventricle/left ventricle+septum weight ratio (RV/LV+S) was signiﬁcantly increased, which was markedly suppressed in the resveratrol treatment group (control: 0.20±0.03; MCT: 0.52±0.07; resveratrol: 0.31±0.08). Histological analysis also showed that MCT increased medial wall thickness of small pulmonary arterioles (50-100µm), which also was signiﬁcantly suppressed in the resveratrol group (control: 16±5%; MCT: 36±8%; resveratrol: 22±5%). In addition, there was signiﬁcant up-regulation of VEGF expression in the lung with resveratrol (P<0.05) which was down-regulated in MCT-induced pulmonary hypertension . Conclusions: This study suggest the possibility that resveratrol may be used for the prevention or treatment of MCT-induced pulmonary hypertension related to reduction of VEGF. 936-189 Sitaxsentan Improves Time to Clinical Worsening (TCW) in Patients With Pulmonary Arterial Hypertension (PAH) Ronald J. Oudiz, Adaani E. Frost, E. C. Lawrence, N. Galie, Robyn J. Barst, UCLA Medical Center, Torrance, CA, Columbia University College of Physicians & Surgeons, New York, NY Background: Sitaxsentan, an oral, once-daily, highly selective endothelin A receptor antagonist, has been studied in three randomized, double-blind, placebo controlled PAH studies. Here, we report a combined analysis of TCW from these 3 studies. Methods: STRIDE-1 (12 weeks,n=178), STRIDE-2 (18 weeks,n=245) and STRIDE- 4 (18 weeks,n=98) included PAH patients with WHO Class II-IV: idiopathic PAH, PAH associated with connective tissue disease or congenital heart defects. These studies evaluated sitaxsentan doses of 50mg, 100mg, and 300mg. Based on the overall risk- beneﬁt analyses of these trials, 100mg once daily is considered to be the optimal dose and only those patients were evaluated in this analysis. In this analysis, the prospective TCW deﬁnition used in STRIDE-2 and STRIDE-4 was retrospectively applied for STRIDE- 1 i.e. hospitalization for worsening PAH, death, transplantation, initiation of new chronic PAH therapy, or deterioration in WHO functional class and ≥ 15% decrease from baseline in six-minute walk distance. TCW was deﬁned from the date of the ﬁrst dose of study drug until the ﬁrst clinical event. Subjects were censored at discontinuation and at study completion. Results: One hundred forty seven patients were treated with sitaxsentan 100mg and 153 were treated with placebo. Using Kaplan-Meier analysis, sitaxsentan improved TCW compared with placebo (p=0.0145, ﬁgure). Conclusions: Sitaxsentan improves time to clinical worsening in patients with PAH. 936-190 Noninvasive Monitoring of Pulmonary Vascular Resistance Changes in Patients With Pulmonary Hypertension Michael Dandel, Hans Lehmkuhl, Yuguo Weng, Sead Mulahasanovic, Onnen Grauhan, Christoph Knosalla, Roland Hetzer, Deutsches Herzzentrum Berlin, Berlin, Germany Background: The utility of systolic pulmonary arterial pressure (PAPs) measurement by echo-Doppler to evaluate the severity of pulmonary hypertension (PH) is limited because PAPs changes are induced by alterations in both pulmonary vascular resistance (PVR) and stroke volume (SV). Since during ejection the ratio between the right ventricular (RV) pressure and the SV depends on PVR, this pressure/volume ratio may be useful to estimate PVR changes and evaluate PH severity. We tested this hypothesis in order to improve the non-invasive follow-up during PH. Methods: Echo-Doppler SV and mean RV ejection pressure estimations were performed in 32 PH patients prior to invasive pulmonary hemodynamic measurements. Patients had different degrees of PH severity. None of them had intracardiac shunts. The ratio between Doppler-derived mean RV ejection pressure and SV was compared with the invasively calculated PVR. Mean RV ejection pressure was obtained from the sum of the mean pressure gradient between RV and right atrium, calculated from continuous-wave Doppler recordings of tricuspid regurgitation jets and the estimated right atrial pressure. SV was obtained from the product of the time-velocity integral measured with pulsed- wave Doppler at the LV outﬂow tract (LVOT) and the cross-sectional LVOT area. Results: The mean RV ejection pressure/SV ratio varied between 0.39 and 2.17 mmHg/ ml. The correlation between this parameter ratio and the catheter-derived PVR was very high (r = 0.87; p<0.001). It was also better than the correlation between PAPs and PVR (r = 0.52; p<0.01), because end-stage PH patients with low SV showed less or no further PAPs elevation, despite persistent PVR increase. Conclusions: The high correlation between the echo-Doppler derived mean RV ejection pressure/SV ratio and the invasively calculated PVR recommends this non-invasive parameter ratio as a useful tool for the follow-up of PH patients. In contrast to the PAPs, which may underestimate PH severity in end-stage disease, the pressure/volume ratio appears especially valuable during advanced PH, where early recognition of deterioration is essential for further decisions and can improve the timing of listing for transplantation. 936-191 ETA vs. ETB Receptor Selectivity of Endothelin-1 Receptor Antagonists in Human Myocardial Membranes S. Greene, K. Nunley, S. Weber, W. Minobe, M. R. Bristow, University of Colorado Cardiovascular Institute, Denver, CO Background: Endothelin receptor antagonists (ERAs) are in commercial use or development for pulmonary hypertension and resistant systemic hypertension. In most cases, ERA-receptor selectivity has been determined in cells or tissues of non-human origin, in different cell/tissue types for each receptor, or in recombinant receptors that may exhibit anomalous binding characteristics in cellular expression systems. Methods: To measure the afﬁnities of ERAs for ETA vs. ETB receptors in the same human tissue preparation, we performed 125[I]-endothelin-1 receptor binding-cold ligand competition curves in human myocardial membranes prepared from nonfailing and failing left ventricles, and determined the cold ligand dissociation constants (Kis) for ETA and ETB receptors by computer modeling. Assay conditions included 10 µM Gpp(NH)p to eliminate high afﬁnity agonist binding, 18 point competition curves between 1 pM and 100 µM, and a 4 hour incubation to achieve steady state binding. Results: The afﬁnities (Ki in nM ± SEM) of ERAs for ETA and ETB receptors, as well as the mean ETA selectivity (fold) are presented below. Conclusions: In human myocardial membranes, 1) bosentan exhibits moderate ETA-selectivity and; 2) BQ-123, sitaxsentan, darusentan and ambrisentan are highly ETA-selective, with ambrisentan exhibiting a >4000-fold higher binding afﬁnity for ETA receptors. This homogeneous system may provide a more reliable estimate of relative receptor afﬁnity and selectivity for various ERAs. ERA Ki, ETA (nM) Ki, ETB (nM) ETA Selectivity, (fold) Bosentan (n = 8) 0.156 ± 0.051 23.5 ± 3.8 242 ± 49 Darusentan (n = 8) 0.178 ± 0.055 216 ± 85 1181 ± 149 Ambrisentan (n = 8) 0.012 ± 0.004 41.8 ± 10.7 4703 ± 625 Sitaxsentan (n = 8) 20.1 ± 5.7 12301 ± 2323 893 ± 201 BQ-123 (n = 6) 2.28 ± 0.96 3260 ± 733 2092 ± 513 ACC_2006_8_VascularDisease.indd 307 1/4/06 5:21:00 PM 308A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n POSTER SESSION 937 Myocardial and Vascular Injury Sunday, March 12, 2006, 1:30 p.m.-5:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 1:30 p.m.-2:30 p.m. 937-192 Combination Therapy With Motexaﬁn Gadolinium and Ascorbate Stabilizes Plaques in Fat-Fed Apolipoprotein E Knockout Mice Yi-Ping Sun, Quan Zheng, Richard Miller, Wai-Fung Cheong, Pharmacyclics, Inc, Sunnyvale, CA Background: Vascular inﬂammation triggers vulnerable plaque rupture. A novel redox cycling agent, motexaﬁn gadolinium (MGd), localizes in plaque and induces apoptosis by generating reactive oxygen species. Previous data showed that MGd plus ascorbate (Asc) selectively depletes macrophages (Mac) without affecting plaque burden in rabbit atheromas. Methods: We evaluated the effects of MGd and Asc on unstable plaques in fat-fed ApoE knockout (KO) mice. After 10-wk fat diet, 72 mice were randomized to control, MGd (20mg/kg IV), Asc (200mg/kg IV), MGd+Asc, MGd 4h post-Asc or MGd 4h pre-Asc (single or 4 biweekly doses), and euthanized 8 wks post 1st dose. Heart-aortas were assessed for intima/media ratios (I/M-R; Verhoeff stain), collagen content (CC; Picrosirius red), Mac (Ab-1), and smooth muscle cells (SMC; actin). MGd uptake and synergism with Asc were studied in human vascular cells in vitro. Results: MGd/Asc signiﬁcantly reduced Mac (p<0.001), decreased I/M-R (best effect with MGd+Asc, p=0.022) and increased CC (40.4% vs control 25.4%, p=0.016), but no obvious differences in SMC, lipids, liver and kidney functions among the groups, suggesting favorable plaque stabilization. In vitro data showed ~4x higher cellular uptake of MGd in Mac and an ampliﬁcation of MGd/Asc cytotoxicity compared to SMC. Conclusions: Combinations of MGd and Asc decreased Mac burden and I/M-R, and stabilized plaques in fat-fed ApoE KO mice. These ﬁndings support a potential new approach for treatment of vulnerable plaque. 937-193 Adiposity and Atherogenic Inﬂammatory Response to Endotoxin in Humans Nehal N. Mehta, Paul Anderson, Megan Wolfe, Michael Rickels, Babette Zemel, Christine Hinkle, Jennifer Tabita-Martinez, Rexford Ahima, Kim Sellers, Daniel J. Rader, Muredach P. Reilly, University of Pennsylvania, Philadelphia, PA Background: A convergence of inﬂammatory and adipose signals may link metabolic syndrome and atherosclerosis. We hypothesized that the degree of adipose tissue may inﬂuence the atherogenic response to acute inﬂammation in vivo in humans. Methods: During a 60-hour inpatient protocol, serial whole blood and adipose (subcutaneous fat biopsies) gene expression, and plasma inﬂammatory markers were measured before and after intravenous bolus of 3 ng/kg endotoxin (LPS) in 20 healthy human volunteers [50% male, 80% Caucasian, age 27.3±4.8; 10 lean (BMI=20.5+1.7), 10 overweight (BMI=27.1+0.9)]. Repeated measures analysis of variance was applied to the data. Results: We observed increases [median fold increase] in adipose gene expression of interleukin-6 (IL-6) [100 fold], tumor necrosis factor-alpha (TNF-alpha) [3.8], PPAR-gamma [2.5], a reduction in fatty acid synthase [60%] and lipoprotein lipase [40%] (p< 0.01 for all), and no signiﬁcant change in adiponectin following LPS. In fact, there was evidence of differential LPS effects on leukocyte versus adipose expression of IL-6 [adipose 100 fold versus leukocyte 4 fold] and TNF-alpha [4 fold versus 10 fold]. We observed marked increases in plasma levels of multiple cardiovascular risk biomarkers including soluble TNF receptor-2 [5.7 fold], C-reactive protein [44.5], E-selectin [9.9], soluble vascular cellular adhesion molecule-1 [2.5], soluble intercellular adhesion molecule-1 [2.2], matrix metalloproteinase-9 [241] and plasminogen activating inhibitor-1 [11.8] (p<0.001 for all). Changes in E-selectin [overweight 130±17; lean 103±9: p=0.09], soluble vascular cellular adhesion molecule-1 [1045±143; 818±77: p=0.09], C-reactive protein [50±27; 38±13: p=0.1] and soluble intercellular adhesion molecule-1 [96±20; 79±15: p=0.26] (all in ng/ mL) tended to be higher in overweight subjects. Conclusions: Adipose signaling pathways are activated during endotoxemia in humans, suggesting that adipose may directly inﬂuence innate inﬂammatory response. Indeed, the degree of adiposity may correlate with the extent of inﬂammation. This provides novel insight into the role of adiposity in pro-inﬂammatory atherogenic responses. 937-194 Absence of Correlation Between Lipid-Lowering Effects and Impacts on Progressive Insulin Resistance in Statin Treatment of a Type-2 Diabetes Model Koji Ohmori, Yan Chen, Mizuki Mizukawa, Kaori Shinomiya, Akira Oshita, Hiroto Takeuchi, Junji Yoshida, Hiroaki Kosaka, Masakazu Kohno, Kagawa University School of Medicine, Miki-cho, Japan Background: Pravastatin was shown to prevent new onset diabetes mellitus (DM). Although lipid-lowering effects, especially triglyceride lowering, was hypothesized to be one of the mechanisms, no evidence for this or other mechanisms have been reported. Therefore, we compared two statins with different strength of lipid-lowering effects in a model spontaneously developing type-2 DM. Methods: Otsuka Long-Evans Tokushima Fatty (OLETF) rats were either untreated (control) or treated with 100 mg/kg/day of pravastatin (PS) or atorvastatin (AS) from 6 weeks of age until 30 weeks. Fasting lipid proﬁles and an index for insulin resistance (IR) as the product of fasting blood glucose and insulin concentrations were followed-up. Effects on cardiac expression of endothelial nitric oxide (NO) synthetase (eNOS), plasma NO concentration, and adipocytokine proﬁles were also compared. Results: Although AS exhibited marked lipid-lowering effects, only PS limited the increase in IR. Cardiac eNOS protein content was higher in PS (2.6 fold of control) than AS (1.5 fold). Plasma NO was higher only in PS. Expression of adiponectin mRNA in adipose tissue was increased only in PS (1.5 fold) than control, which was accompanied by elevated plasma adiponectin and suppressed TNF-� levels in PS-treated OLETF rats (Table). Conclusions: Preventive effect of statins on progression of insulin resistance is independent of lipid-lowering effects but may be related to the impacts on eNOS availability and adipocytes behavior. Plasma levels of variables at 30 weeks, *p<0.05 vs. OLETF, #p<0.05 vs. PS-OLETF TG (mg/dL) IR (mg/dL*U/L) NOx (µmol/L) adiponectin(µg/ mL) TNF-α (pg/ mL) OLETF 202±54 593±175 14.3±2.6 3.0±0.7 17.4±6.2 PS-OLETF 130±35* 416±136* 18.2±3.0* 4.0±0.9* 12.7±4.3* AS-OLETF 53±21*# 643±184# 15.5±2.1 3.0±0.5# 16.8±5.7 937-195 Ghrelin Protects Myocardium Against Ischemia/ Reperfusion Injury via Inhibiting Myocardial Apoptosis Takeshi Soeki, Yamato Fukuda, Kunihiko Koshiba, Koji Yamaguchi, Tomohito Kawano, Hirotsugu Yamada, Tetsuzo Wakatsuki, Masahiro Nomura, Kenji Kangawa, Susumu Ito, University of Tokushima, Tokushima, Japan, National Cardiovascular Center Research Institute, Suita, Japan Background: Ghrelin is a novel growth hormone-releasing peptide originally isolated from the stomach. Recent study suggests that ghrelin inhibits various cell death through extracellular signal-regulated kinase-1/2 and Akt serine kinases in vitro. However, the effect of ghrelin on myocardial ischemia/reperfusion remains unknown in vivo. We hypothesized that ghrelin administration would attenuate myocardial ischemia/reperfusion injury through its anti-apoptotic activity. Methods and Results: Male Sprague-Dawley rats were exposed to a 30-minte period of ischemia induced by ligation of the left coronary artery. They were randomized to receive ghrelin or saline for 60 minutes after coronary ligation. Hemodynamics and infarct size were examined 24 hours after reperfusion. For detection and quantiﬁcation of apoptosis, gel electrophoresis of extracted genomic DNA and the terminal dUTP nick-end labelling (TUNEL) method of parafﬁn sections were performed. Intravenous administration of ghrelin signiﬁcantly reduced left ventricular end-diastolic pressure (19+/-3 to 10+/-3 mmHg, P<0.01) and myocardial infarct size (32+/-5% to 21+/-3, P<0.01). Furthermore, TUNEL-positive myocytes were less frequently observed in the ghrelin-treated group than in the saline-treated group. Although a typical DNA ladder indicating fragmented DNA in cardiomyocytes was also observed in the saline-treated group, it was attenuated in the ghrelin-treated group. Conclusions: Ghrelin infusion attenuates myocardial ischemia/reperfusion injury. This effect might be attributed to anti-apoptotic effect of ghrelin. These data suggest the potential usefulness of ghrelin as a new cardioprotective agent. 937-196 Clopidogrel Withdrawal Is Associated With Pro- Inﬂammatory Effects in Patients With Diabetes Mellitus Dominick J. Angiolillo, Esther Bernardo, Celia Ramirez, Manel Sabate, Pilar Jimenez- Quevedo, Antonia Rodriguez de la Pena, Raul Moreno, Fernando Alfonso, Rosana Hernandez-Antolin, Marco A. Costa, Theodore A. Bass, Antonio Fernandez-Ortiz, Carlos Macaya, University of Florida-Shands Jacksonville, Jacksonville, FL, San Carlos University Hospital, Madrid, Spain Background: Inhibition of the platelet P2Y12 pathway by clopidogrel (C) has shown to have anti-inﬂammatory effects in the acute phases of treatment. However, if C withdrawal ACC_2006_8_VascularDisease.indd 308 1/4/06 5:21:00 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 309A Vascular D isease, H ypertension, and P revention is associated with pro-inﬂammatory effects is unknown. Since diabetic (D) patients (pts) have an enhanced inﬂammatory status, we hypothesized that these pts may be more vulnerable to these effects. Aim of the study: to assess the impact of C withdrawal on markers of inﬂammation in D pts. Methods: 54 type II D pts were studied. All pts were on long-term (12 month) combined aspirin (ASA, 100mg/d) + C (75mg/d) therapy. Markers of inﬂammation were assessed before and one-month following C withdrawal. Inﬂammatory markers included assessment of high sensitivity C-reactive protein (hsCRP) by nephelometry and cell surface P-selectin expression (CD62-P) in resting platelets and after ADP (2µM) stimuli by whole blood ﬂow cytometry. Results: A signiﬁcant increase in all the inﬂammatory markers was observed following C withdrawal (Table). hsCRP values are expressed as median and interquartile range. CD- 62P values are expressed as % of positive platelets. ASA+Clopidogrel ASA p-value hs-CRP (mg/dL) 0.30 (0.16-0.54) 0.39 (0.18-0.69) <0.05 P-selectin (resting) 10.9 (4.2-24.8) 24.3 (6.4-47.5) <0.001 P-selectin (ADP-stimulated) 28.3 (18.9-42.6) 63.5 (46.3-72.7) <0.0001 Conclusions: C withdrawal is associated with an increase in markers of inﬂammation in D pts. These data support the pleiotropic, anti-inﬂammatory, properties attributed to C which may contribute to the clinical beneﬁt associated with long-term dual antiplatelet treatment, especially in high risk pts. 937-197 Amiodarone and its Metabolite, N-desethylamiodarone, Enhance Endothelial Nitric Oxide Production in Human Endothelial Cells Shinya Kishida, Toshiaki Nakajima, Hitoshi Oonuma, Haruko Iida, Haruhito Takano, Toshihiro Morita, Ryozo Nagai, University of Tokyo, Tokyo, Japan Background: Amiodarone (AMD) is an antiarrhythmic agent noted for its cardiovascular protective effects in vivo. But the underlying mechanisms remain unsettled. The present study investigated the effects of AMD and N-desethylamiodarone (DEA), a major metabolite of AMD, on nitric oxide (NO) production and [Ca2+]i in human umbilical vein endothelial cells (HUVECs). Methods: The release of NO was evaluated as measured by nitrite, using Griess reaction and directly by NO-selective electrode. The effects of AMD on endothelial NO synthase (eNOS) mRNA expressions were investigated by the quantitative real-time RT-PCR. [Ca2+]i was evaluated using fura-2 AM. Apoptosis was examined by the cell death assay system kit using Hrp-DAB. Results: AMD and DEA (1-30 µM) induced NO production in a concentration-dependent manner, while co-administration with L-NAME, EGTA or Ni2+ suppressed it. The potency was DEA>AMD. AMD and DEA at 1-10 µM for 24 h signiﬁcantly increased NO production, while they did not stimulate LDH release from cells or cause apoptotic effects. Treatment with AMD for 24-48 h did not increase eNOS mRNA expression signiﬁcantly. DEA (3-10 µM) signiﬁcantly increased [Ca2+]i. Conclusions: The present study provides the ﬁrst novel evidence that therapeutic concentrations of AMD and its metabolite produce eNOS-mediated NO production, possibly via increase in [Ca2+]i in human endothelial cells; toxic or apoptotic effects were NOT observed at the above-mentioned concentrations. These actions appear to contribute to the cardiovascular protective effects of amiodarone. POSTER SESSION 938 Antihypertensive and Antiarrhymic Agents: Hemodynamic and Clinical Effects Sunday, March 12, 2006, 1:30 p.m.-5:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 1:30 p.m.-2:30 p.m. 938-198 The Effectiveness of Blinding of an Active Angiotensin Converting Enzyme Inhibitor at a Single Center in the Prevention of Events With Angiotensin Converting Enzyme Inhibition (PEACE) Trial Ellis W. Lader, Martha Meyer, Paul Reiter, Gary Cohen, Dineshkant Parikh, Aneta Dimova, Mid Valley Cardiology, Kingston, NY Background: Although effective blinding of a therapeutic intervention is considered essential to eliminating bias in a randomized clinical trial, the ability to successfully blind an angiotensin converting enzyme inhibitor (ACE-I) has not been reported. Methods: At our center in the PEACE trial, 58 patients were randomized to active agent (trandolapril, target dose 4 mg daily) or placebo. All were able to tolerate the ACE-I during an unblinded “run-in” phase. By the end of the trial, 6 died and 2 were unsure of their drug assignment; the remaining 50 all felt they knew with certainty if they were receiving either active ACE-I or placebo. At the conclusion of the trial we compared their beliefs with their actual drug assignment; we assumed the null hypothesis was being correct 50% of the time, and evaluated their results using the two-tailed one-sample Z test. Results: n Percent correct P value Total 50 46% 0.57 Receiving placebo 23 30% 0.002 Receiving ACE-I 27 59% 0.19 Males 39 54% 0.99 Females 11 18% 0.008 On diuretics 12 42% 0.57 Under 75 years old 31 58% 0.37 75 years old and over 19 32% 0.09 Conclusions: In the subset of PEACE study patients seen at our center, no patient group could correctly identify their drug assignment better than by chance. This implies that blinding of an ACE-I can be effective and that patient bias can be effectively eliminated in ACE-I trials. 938-199 Effect of Amlodipine and Enalapril on Cardiovascular Events in Patients With Insulin Resistance and Diabetes in the CAMELOT Trial Sarkis B. Baghdasarian, Paul D. Thompson, Harry Shi, Kamlesh M. Thakker, Murat E. Tuzcu, Steve Nissen, Henry Low Heart Center, Hartford Hospital, University of Connecticut, School of Medicine, Hartford, CT, The Cleveland Clinic Foundation, Cleveland, OH Background: We used the CAMELOT database to explore the effect of treatment with amlodipine or enalapril on cardiovascular (CV) events in patients with diabetes mellitus (DM), metabolic syndrome (MS), and impaired fasting glucose (IFG). Methods: CAMELOT was a double-blind, randomized controlled trial comparing amlodipine 10 mg daily or enalapril 20 mg daily with placebo in 1991 patients with angiographically documented coronary artery disease and diastolic blood pressure <100 mm Hg. Of the 1991 patients, 363 had DM, 822 had MS, and 350 had IFG. The log-rank test and Cox proportional hazards model were used. CV events evaluated included the primary endpoint (Major Adverse CV Event, MACE) and its components. Results: Baseline demographics were similar in the three treatment arms of patients with DM, MS or IFG. In patients with DM, amlodipine signiﬁcantly reduced MACE compared to enalapril (hazard ratio [HR]= 0.58, p= 0.043). In patients with MS, amlodipine signiﬁcantly reduced MACE compared to placebo (HR= 0.62, p=0.015), and enalapril (HR= 0.59, p= 0.008). In patients with IFG, amlodipine signiﬁcantly reduced MACE compared to placebo (HR= 0.47, p=0.018), but enalapril did not (table). Conclusion: Amlodipine signiﬁcantly reduced cardiovascular events in normotensive coronary artery disease patients with diabetes and metabolic syndrome compared to enalapril. Amlodipine also signiﬁcantly reduced such events in patients with metabolic syndrome and impaired fasting glucose compared to placebo. Subgroup / Outcome Amlodipine Enalapril Placebo Amlodipine vs. placebo Amlodipine vs. enalapril Enalapril vs. Placebo Event rate (%) Event rate (%) Event rate (%) HR P HR P HR P DM (N=363) MACE 22/115 (19.1%) 35/118 (29.7%) 38/130 (29.2%) 0.62 0.067 0.58 0.043 1.06 0.796 MS (N=822) MACE 43/288 (14.9%) 62/265 (23.4%) 61/269 (22.7%) 0.62 0.015 0.59 0.008 1.052 0.779 IFG (N=350) MACE 15/127 (11.8%) 19/106 (17.9%) 27/117 (23.1%) 0.47 0.018 0.64 0.192 0.75 0.339 938-200 Efﬁcacy and Safety of Extra Class IC Doses for Pharmacologic Cardioversion in Patients Maintained on Class IC Drugs for Atrial Fibrillation James A. Reiffel, Columbia University, New York, NY, Guglielmo da Saliceto General Hospital, Piacenza, Italy Background: The class IC antiarrhythmic drugs (AAD) propafenone, in the immediate release form tid (P-IR) and sustained release form bid (P-SR), and ﬂecainide (F) bid are often used to reduce or prevent episodes of atrial ﬁbrillation (AF), especially in patients (pt) without structural heart disease or uncomplicated hypertension, and may be initiated in the out-pt setting. The usual maximal daily doses (MDD) are: P-IR 900 mg/d; P-SR 850 mg/d; F 400 mg/d. P-IR at 450 mg/d and 675 mg/d approximates the PK curves of P-SR at 650 mg/d and 850 mg/d. Additionally, single doses of P-IR (usually 600 mg) and F (usually 300 mg) have been used to terminate recent-onset AF in pt not taking an AAD, with efﬁcacy rates of 70-80% by 8 hrs. Methods: To determine whether extra doses of P-IR of F could be used to convert recurrent AF in pt already taking daily P-IR, P-SR, or F (but less than the MDD), 45 pt (average age 49 yrs) with 63 episodes were given extra out-pt doses of P-IR or F at least 3 hrs after their prior drug dose to increase their total dose of P or F for that day (to not exceed MDD). For example, P-IR 600 mg/d: a 300 mg “bolus” dose was used; for P-IR 450 mg/d: a 300 mg was used, followed in 4 hrs by another 150 mg if needed. For P-SR at 325 mg bid: a 300 mg of P-IR was used, but for P-SR 425 mg bid, no more than 150 mg P-IR was used. All new AF episodes were <24 hrs long prior to the extra dosing. Pts in Italy (It) (n=22) were ECG monitored continuously. Results: for daily maintenance/acute dosing: 11 pt used F/F, 13 pt used P-SR/P-IR, and 21 pt used P-IR/P-IR. Conversion rates were 64% (n=7), 77% (n=10), and 62% (n=13) respectively. Four It pts developed transient ﬂutter (3/4 converted to NSR). Adverse effects were mild (e.g., nausea, visual blurring, vague dizziness); there was no syncope, undue bradycardia, or ventricular tachyarrhythmia. ACC_2006_8_VascularDisease.indd 309 1/4/06 5:21:01 PM 310A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n Conclusions: P-IR “bolus” dosing can be used to terminate recurrent AF in pt taking daily P-IR or P-SR as can F in pts taking F, using the MDD as a guide to total dosing. Efﬁcacy rates approach those in pts not yet taking a daily AAD. Such additional doses appear to be as well tolerated as they are in pt not taking daily AAD. 938-201 Effect of Metoprolol CR/XL on Pulmonary Artery Pressure in Patients With Heart Failure Measured Using First in Human Implantable Device Responding to Ultrasonic Signal Keyur H. Parikh, Hetal D. Shah, Milan C. Chag, Urmil G. Shah, Hemang A. Baxi, Anish H. Chandarana, Ajay M. Naik, Joyal N. Shah, Yoseph Rozenman, Finn Waagstein, Ake Hjalmarson, The Heart Care Clinic, Ahmedabad, India, Goteberg University, Goteberg, Sweden Background: Beta blockers (BB) do improve morbidity and mortality in patients with Congestive Heart Failure(CHF).There is limited information on Left Ventricular End Diastolic Pressure,Pulmonary artery pressure(PAP) including PADiastolic Pressure(PADP) after the use of BB in ambulatory patients with CHF. Frequent, noninvasive, monitoring of PADP, provides necessary direction of therapy in CHF. Remon CHF Implant (Remon Technologies, Israel) is a ﬁrst of its kind , implantable device responding to ultrasonic signals for the noninvasive monitoring of PAP.The study investigates the effect of Metoprolol CR/XL(MXL) on the PADP as monitored by the Implant. Methods: It was a First-in-Man, prospective,single arm study. 10 NYHA class III/IV CHF patients with LVEF 26.5±4.3 % were enrolled for the Remon CHF(3mmx3mmx16mm) implantation, a device placed percutaneously via internal jugular vein, permanently in the Right PA.Using ultrasonic signals, it generates the PAP waveforms on a desktop system. PAP were measured for the ﬁrst month without any BB therapy.The patients were then loaded with MXL 25mg/day and uptitrated two weekly using the MERIT-HF criteria. PAP/ PADP were regularly monitored. Results: The mean baseline PAP of the patients were 33.22(±11.54) mm Hg systolic and 17.24(±8.27) mm Hg diastolic before giving MXL.The mean baseline systemic blood pressure(BP) and heart rate(HR) were 113(±18)mmHg systolic,72(±7) mmHg diastolic and 83(±13)beats/min. After 2 weeks of 25 mg/d MXL , the mean PAP rose to 36.55(±13.2)mm Hg systolic and 19.37(±9.8) mmHg diastolic(p=NS) .After uptitration to 50mg MXL, the mean PAP rose to 36.28(±7.9) mm Hg systolic(p=0.03) and 17.7(±5.9) mmHg diastolic(p=0.12). Mean systemic BP and HR did not show any signiﬁcant change.One patient had to be discontinued from MXL due to symptomatic rise of PADP, subsequently normalised by I.V. diuretics. Long term effects of upto 200 mg MXL (as tolerated) will also be evaluated at 3 months and 6 months. Conclusions: Loading Metoprolol CR/XL in CHF patients shows early rise in the PAP and PADP as meaured by this innovative Implant. This supports the recommendation for slow and careful up-titration of MXL in CHF patients. 938-202 Effect of Amlodipine and Enalapril on Cardiovascular Events in Normotensive Coronary Artery Disease Patients with Concomitant Statin Use in the CAMELOT Trial Sarkis B. Baghdasarian, Paul D. Thompson, Harry Shi, Kamlesh M. Thakker, Murat E. Tuzcu, Steve Nissen, Henry Low Heart Center, Hartford Hospital, University of Connecticut, School of Medicine, Hartford, CT, The Cleveland Clinic Foundation, Cleveland, OH Background: We used the CAMELOT database to investigate the effect of treatment with amlodipine, enalapril or placebo on cardiovascular (CV) events in the group of patients receiving concomitant statin therapy, and in the subgroups receiving atorvastatin or simvastatin. Methods: CAMELOT was a double-blind, randomized controlled trial comparing amlodipine 10 mg daily or enalapril 20 mg daily with placebo in 1991 patients with angiographically documented coronary artery disease and diastolic blood pressure <100 mm Hg. The log-rank test and Cox proportional hazards model were used. CV events evaluated included the primary endpoint (Major Adverse CV Event, MACE) and its components. Results: In patients with concomitant statin therapy (N=1653), MACE occurred in 24.5% of placebo-treated patients and 16.9% of amlodipine-treated patients (hazard ratio [HR]= 0.66, p=0.002); and 21.8% of enalapril-treated patients (table). The reduction in MACE with amlodipine vs. placebo was signiﬁcant only with concomitant atorvastatin (HR=0.63, p=0.029). Amlodipine also reduced MACE compared to enalapril with concomitant statin therapy (HR= 0.74, p= 0.030). Conclusion: Amlodipine 10 mg daily for 2 years signiﬁcantly reduced the risk of major adverse cardiovascular events compared to placebo and enalapril in normotensive patients with coronary artery disease on a concomitant statin. The beneﬁt versus placebo was primarily due to concomitant atorvastatin in amlodipine-treated patients. Subgroup / Outcome Amlodipine Enalapril Placebo Amlodipine vs. placebo Amlodipine vs. enalapril Enalapril vs. Placebo Event rate n (%) Event rate n (%) Event rate n (%) HR P HR P HR P Any Statin (N=1653) MACE 93/551 (16.9%) 120/550 (21.8%) 135/552 (24.5%) 0.66 0.002 0.74 0.030 0.89 0.351 Atorvastatin (N=727) MACE 35/225 (15.6%) 52/264 (19.7%) 56/238 (23.5%) 0.63 0.029 0.75 0.191 0.83 0.347 Simvastatin (N=552) MACE 40/194 (20.6%) 39/170 (22.9%) 51/188 (27.1%) 0.74 0.153 0.89 0.589 0.83 0.378 938-203 Urocortin 2 Infusion in Healthy Humans Induces Marked Hemodynamic, Neurohormonal, and Renal Responses Mark E. Davis, Christopher J. Pemberton, Timothy J. Yandle, John G. Lainchbury, Christopher M. Frampton, Miriam T. Rademaker, Mark Richards, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand Background: Urocortin 2 (Ucn2) is a recently discovered vasoactive peptide belonging to the corticotrophin releasing factor peptide family. Recent reports indicate that Ucn2 administration in animals exerts important effects beyond the hypothalamo-pituitary- adrenal axis which impact directly upon cardiac, vascular and the vaso-humoural function in health and cardiac disease. We report the ﬁrst controlled study in healthy human volunteers to examine the effects of urocortin 2 on hemodynamic status, cardiovascular hormones and renal function. Methods: On day 3 of a controlled metabolic diet we studied 8 healthy male volunteers on three separate occasions 2-5 weeks apart. Subjects received placebo, 25µg low dose (LD) and 100µg high dose (HD) of Ucn2 intravenously over one hour in a single blind, placebo-controlled, dose-escalation design. Non-invasive hemodynamic indices, neurohormones and renal function were measured. Results: Ucn2 administration dose-dependently increased cardiac output (maximal increments relative to baseline (±SEM): placebo 0.5±0.2; LD 2.1±0.6; HD 5.0±0.8 L/ min, P<0.001), heart rate (placebo 3.3±1.0; LD 8.8±1.8; HD 17.8±2.1 beats per minute, P<0.001) and left ventricular ejection fraction (LVEF) (0.6±1.4; LD 6.6±1.5; HD 14.1±0.8 %, P<0.001) while decreasing diastolic blood pressure (maximal decrement relative to baseline: placebo 4.9±1.2; LD 7.4±1.5; HD 14.1±2.1 mmHg, P<0.001) and systemic vascular resistance (SVR) (placebo 128±50; LD 407±49; HD 774±133 dynes*sec/cm5, P<0.001). Activation of plasma renin activity (P=0.002), angiotensin II (P=0.001) and norepinephrine; (P<0.001) occurred only with the higher 100µg dose. Ucn2 induced dose- related decreases in urinary volume (P=0.012) and excretion of sodium (P=0.001) and potassium (P<0.001). Conclusions: Brief intravenous infusions of Ucn2 in normal humans provoked marked dose-related increases in cardiac output, heart rate and LVEF in association with decreased SVR. Neurohormonal and renal responses were observed, but it is unclear whether are they are purely a secondary response to hemodynamic perturbation or are partly due to direct effects of Ucn2 upon the kidney and/or adrenal. POSTER SESSION 939 Metabolic Syndrome: A Growing Concern Sunday, March 12, 2006, 1:30 p.m.-5:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 1:30 p.m.-2:30 p.m. 939-204 Global Risk Assessment of U.S. Persons With the Metabolic Syndrome Khiet Hoang, Victor A. Lopez, Michael A. Barboza, Nathan D. Wong, University of California, Irvine, Irvine, CA Background: The metabolic syndrome (MetS) comprises individuals with a wide spectrum of risk for coronary heart disease (CHD). We estimated the 10-year CHD risk among U.S. persons with the metabolic syndrome (MetS). Methods: The prevalence of MetS as deﬁned by the modiﬁed National Cholesterol Education Program deﬁnition was evaluated in U.S. adults aged 20-79 in the National Health and Nutrition Examination Survey (NHANES) 2001-2002. 10-year risk for CHD was calculated using the Framingham risk algorithms. Very low, low, intermediate, and high risk status were deﬁned by < 6%, 6-10%, 10-20%, and > 20% probability of CHD in 10 years, respectively; those with diabetes or pre-existing CHD were assigned to high risk status. Results: MetS prevalence was 27.5% in men and 28.6% in women (p=.53). The table below shows the distribution of CHD risk among persons with MetS, overall and by gender and ethnicity: Distribution of 10-Year Risk for CHD in U.S. Persons with Metabolic Syndrome Group N (weighted N, in millions [M]) Very low (<6%) Low (6-9%) Intermediate (10-20%) High (>20%) High w/DM or CVD Overall 1026 (39.7 M) 41.4% 10.8% 15.2% 3.1% 29.8% Males 488 (19.4 M) 30.7% 12.0% 21.5% 5.1% 30.7% Females 538 (20.3 M) 51.1% 9.6% 9.2% 1.1% 29.0% Black 187 (3.8 M) 40.6% 8.1% 4.6% 2.3% 44.4% Hispanic 289 (5.4 M) 49.9% 8.8% 8.9% 2.2% 30.2% White 515 (28.5 M) 39.5% 12.0% 17.3% 3.5% 27.7% Among those with MetS, 52% were very low or low risk, 15% intermediate risk, and 33% high risk (including DM/CVD). Among race, the proportion of those with MetS at high risk was 47%, 32%, and 31% for blacks, Hispanics, and whites, respectively (p<.01). Conclusions: While about half of MetS patients are at an intermediate or high calculated risk for CHD, many are at low risk. Of note, more than half of men and blacks are at intermediate or high risk status. These ﬁndings reinforce the need for global risk assessment in persons with MetS to more appropriately target intensity of treatment for underlying risk factors. ACC_2006_8_VascularDisease.indd 310 1/4/06 5:21:01 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 311A Vascular D isease, H ypertension, and P revention 939-205 The Applicability of the Asian Modiﬁed Criteria of the Metabolic Syndrome in the Asian Population Jae-Youn Moon, Sungha Park, Sun Ha Jee, Chan Mi Park, Dae-Sik Choi, Hyun-Young Park, Young-Guk Ko, Donghoon Choi, Yangsoo Jang, Namsik Chung, Cardiovascular Center, Cardiovascular Genome Center, Cardiovascular Hospital, Seoul, South Korea Background: No published data exists regarding the difference in the prevalence, the degree of insulin resistance and the risk of CAD when the Asian criterias for Metabolic syndrome(MetS) are applied compared to the conventional criteria. We compared the metabolic proﬁles and risk of CAD in Koreans with non-diabetic MetS when applying the 4 criterias of MetS.[The NCEP criteria, Asian modiﬁed NCEP(a-NCEP) criteria, WHO criteria, Asian modiﬁed WHO(a-WHO)]. Methods: The study group composed of non-diabetic 2724 subjects. There were 728 patients with signiﬁcant CAD. The different criterias of MetS was applied for the study populations. The prevalence of the MetS and the statistical value of CAD prediction by using different criteria were estimated. The lipid proﬁle, serum apolipoproteinA(apoA) level, apolipoproteinB(apoB) level, and insulin resistance(HOMA index) was compared between the participants who were classiﬁed to MetS by using different criterias. Results: Among the 2724 participants, 522(19.2%) met the NCEP criteria, 796(29.2%) met the a-NCEP criteria, 361(13.3%) met the WHO criteria, 576(21.1%) met the a-WHO criteria. The clinical parameters, lipid proﬁle, apoA1 and apoB level were not different between the participants classiﬁed as MetS by using different criteria. The odds ratio for CAD prediction were not signiﬁcantly different according to the metabolic criteria(Odd ratio: 1.755 [95% CI; 1.423-2.163] in NCEP criteria, 2.120 [1.763-2.549] in a-NCEP criteria, 1.854 [1.466-2.343] in WHO criteria, 2.205 [1.810-2.687] in a-WHO criteria). The serum level of apoA1 and apoB showed strong correlations with MetS classiﬁed by all criteria and the HOMA index and insulin level showed better correlations with WHO-MetS criteria. Conclusions: All the MetS criterias showed similar metabolic proﬁles and the ability for CAD prediction were similar between the 4 criterias. Conventional MetS criteria, applied to non-diabetic Asian population, may underestimate the population at risk. Our data suggests that the Asian modiﬁed criteria will decrease the risk for underdiagnosis while demonstrating similar metabolic proﬁles and CAD risk compared to the conventional criterias. 939-206 The Metabolic Syndrome but Not Estimated Insulin Resistance Is Associated With Higher-Risk of Adverse Clinical Outcomes Among Medically Managed Patients Following Cardiac Catheterisation NIck Newall, Roger Moore, Paul Browning, Rodney H. Stables, Mark Jackson, Cheng Hock Toh, Alan Shenkin, David Ramsdale, The Cardiothoracic Centre, Liverpool, United Kingdom, The Royal Liverpool and Broadgreen University Hospital, United Kingdom Background: Insulin resistance (IR) has been suggested as a common mechanism for the development of the metabolic syndrome (MS) and atherosclerosis. Aims: To assess the prognostic importance of MS and IR among patients with suspected coronary disease. Method: We conducted a prospective cohort study of 2444 patients undergoing cardiac catheterisation (CC). The MS was deﬁned by the National Cholesterol Education Program criteria. Fasting glucose, and insulin levels were used to estimate IR by the homeostasis model assessment (HOMA). Patients were followed for death, nonfatal myocardial infarction (MI), or re-hospitalisation with chest pain until revascularisation or one year. Cox proportional hazard test was used to determine independent associations with outcome. Results: 2009 patients had complete data, did not receive insulin therapy or immediate revascularisation. 510 (25.4%) had the MS. There were 234 (9.6%) endpoints. The variables independently associated with avderse clinical otcomes are given in the table. The MS was independently associated with adverse outcome, HOMA IR was independently associated with better outcome. Conclusions: The metabolic syndrome is highly prevalent among patients undergoing cardiac catheterisation and associated with higher risk of subsequent death MI or rehospitalaisation with chest pain. This association is not explained by fasting hyperinsulinaemia, which among this cohort was independently associated with better clinical outcomes. Independent predictors of death, MI or readmission with chest pain Hazard Ratio (HR) 95% CI for HR lower 95% CI for HR lower Signiﬁcance (p) Left Ventricular Ejection Fraction (%) 0.984 0.975 0.993 0.001 Unstable Symptoms 2.021 1.536 2.660 <0.001 Metabolic Syndrome 1.447 1.074 1.952 0.015 HOMA Insulin Resistance 0.881 0.827 0.939 <0.001 Aortic stenosis 1.858 1.151 3.002 0.011 Number of coronary vessels with75% or more stenosis 1.189 1.032 1.371 0.017 Non insulin dependent diabetes 1.533 1.064 2.211 0.022 939-207 Long-Term Result of Metabolic Syndrome with Patients Undergoing Coronary Artery Bypass Grafting Kan Kajimoto, Takatoshi Kasai, Katsumi Miyauchi, Hiroshi Niinami, Atsushi Amano, Hiroyuki Daida, Juntendo, Juntendo University, Tokyo, Japan Background: Metabolic syndrome (MS) is regarded as a key risk factor for coronary artery disease. However, few reports are available on the relationship between MS and long-term result after coronary artery bypass graft (CABG). Methods: 722 consecutive patients who underwent CABG were studied. Patients were classiﬁed into 2 groups depending on the presence or absence of MS using the NCEP- ATPIII deﬁnition (for obesity we used a body mass index≥25 kg/cm2). Multivariate Cox proportional-hazards regression, adjusted for age, gender, BMI, total cholesterol level, systolic and diastolic blood pressure, diabetes, family history of coronary artery disease, smoking history, previous myocardial infarction, previous stroke, peripheral vascular disease, chronic kidney disease, left ventricular ejection fraction, using vein graft was used to examine the risks for all cause death, cardiac death in the MS group compared with the non MS group. Result: There are 293 patients with MS (41%) and 429 patients without MS (59%). The mean follow-up period was 11 ± 4 years. Overall, there were 239 (33%) deaths from all cause, and there were no signiﬁcant differences between the two groups (35% in the MS, 32% in the no MS: hazard ratio (HR) 1.22; 95% conﬁdence interval (CI)[ 0.92-1.63]; P=0.17). There were 38 (13%) cardiac deaths in the MS group and 38 (9%) in the non MS group (HR 1.67; 95% CI [1.01-2.79]; P=0.04). Conclusion: The presence of the MS signiﬁcantly increased risks of cardiac death in patients undergoing CABG. 939-208 Dysmetabolic Status, and Not Obesity Per Se, Is Associated With Increased Cardiovascular Mortality in Patients With Stable Coronary Disease Kim M. Fox, Caroline Daly, Michel Bertrand, Roberto Ferrari, Willem Remme, Maarten Simoons, on behalf of the EUROPA investigators, Royal Brompton Hospital, London, United Kingdom Background: Obesity is associated with the metabolic syndrome (Met Syn), but the effect of obesity on CV mortality in the population with coronary artery disease (CAD) independent of this association was not clear. Methods: We studied 8397 patients with CAD with 4.2 year follow up from the EUROPA trial. Patients were categorised as dysmetabolic if they had either diabetes or Met Syn. Met Syn was deﬁned by the presence of at least 3 of the following: BP >130/85; HDL <1.0 mmol/l (male), and <1.3 mmol/l (female); Body Mass Index (BMI) > 30; or fasting plasma glucose >6.1 mmol/l. BMI < 25 was considered normal weight, BMI 25-30 overweight and BMI > 30 obese. Results: Met Syn without diabetes was identiﬁed in 1183 patients (14%) and diabetes in 1502 (18%). Stratiﬁed according to BMI and dysmetabolic status, dysmetabolic status but not overweight or obesity increased the risk of CV death (Fig 1.) Compared to normal weight individuals without dysmetabolic features, the RR of CV death associated with obesity and dysmetabolic status was 2.4 [1.5-3.7], overweight and dysmetabolic status 3.0 [1.9-4.7], and normal weight and dysmetabolic status 4.1 [2.9-6.9]. Overweight or obese individuals without diabetes or Met Syn were not at increased risk of CV death. Conclusions: In patients with CAD, obesity is not an independent predictor of CV death. Screening for diabetes and Met Syn should be carried out in all patients with CAD, as dysmetabolic status in those with normal weight is associated with a particularly high risk of CV death. 939-209 Cardiovascular Risk Classiﬁcation in Hypertensive Patients With or Without Metabolic Syndrome: Results From the ICEBERG Study Giray Kabakci, Nevres Koylan, Omer Kozan, Baris Ilerigelen, Kemalettin Buyukozturk, on behalf of the ICEBERG study investigators, Hacettepe University, Ankara, Turkey Background: Metabolic syndrome (MS) is a clustering of metabolic abnormalities associated with increased risk of cardiovascular events and type 2 diabetes. This report focuses on cardiovascular risk classiﬁcation of hypertensive patients enrolled in the Intensive / Initial Cardiovascular Examination regarding Blood pressure levels: Evaluation of Risk Groups (ICEBERG) study in the presence or absence of metabolic syndrome. Methods: ICEBERG is a healthcare organization-based epidemiological study, with two ACC_2006_8_VascularDisease.indd 311 1/4/06 5:21:02 PM 312A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n sub-protocols: at 20 cardiology centers (1) and 197 primary healthcare centers (2). Each protocol had two arms: (A) hypertensive patients on treatment and (B) subjects with ≥130 mmHg systolic or ≥85 mmHg diastolic blood pressure; under no medication for the last 3 months. A total of 4034 patients were included in the analysis. Risk assessment was performed according to ESC-ESH 2003 guidelines and included medical history, physical exam, serum biochemistry and microalbuminuria. Presence of three of the ﬁve components (hypertension, fasting plasma glucose levels or drug treatment for elevated glucose, abdominal obesity, low HDL and high triglyceride levels) was deﬁned as MS. Results: MS was present in 65.0% of the patients. The percentage of patients with MS was 67.5% for patients on treatment (n=3129), and 56.5% for patients not on treatment (n=905). When evaluated for cardiovascular risk, 77.5% of the patients with MS were placed in high or very high added risk group (H/VH), while only 54.3% of the patients without MS were in H/VH. Similarly, a higher percentage of patients with MS, compared to the patients without MS, were in H/VH both for patients on treatment (76.9% vs. 52.1%) and not on treatment (80.0% vs. 60.2%). The percentage of patients in H/VH increased with increasing number of MS components (45.4%, 57.8%, 70.4%, 80.8% and 91.1% of the patients with one, two, three, four and ﬁve MS components, respectively; p<0.001). Conclusion: Although individual components of the MS are accounted for in the current risk assessment guidelines, presence of MS encompassing three or more of these components might indicate a higher added cardiovascular risk for hypertensive patients. 939-210 Progressive Decrease in Large and Small Artery Elasticity With the Presence of Multiple Components of the Metabolic Syndrome Fred M. Wu, Daniel A. Duprez, Natalia Florea, Katherine Jones, Lynn Hoke, Jay N. Cohn, University of Minnesota, Minneapolis, MN Background: There has been considerable controversy surrounding the value of the metabolic syndrome as an independent CVD risk marker beyond that of its individual components. Large (LAE) and small artery elasticity (SAE) have been considered to be early markers of CVD. The aim of this study is to examine the additive effects of the components of the metabolic syndrome on LAE and SAE in patients who meet the diagnostic criteria for metabolic syndrome and age-matched controls. Methods: A total number of 672 subjects without overt cardiovascular disease underwent determination of the large (LAE) and small artery elasticity (SAE) using radial pulse wave contour analysis. Components of the metabolic syndrome were measured according to NCEP criteria and related to large and small artery elasticity by ANCOVA, correcting for age, gender and body-mass index (BMI). Results: Table 1: Mean aterial elasticity indices by group Features of the metabolic syndrome C1 (ml/mmHg * 10) C2 (ml/mmHg * 100) 0 (n=181) 18.8 ± 0.4 7.6 ± 0.2 1 (n=305) 16.8 ± 0.3 6.4 ± 0.1 2 (n=44) 17.0 ± 0.8 6.2 ± 0.4 3 (n=113) 16.4 ± 0.5 6.0 ± 0.3 ≥4 (n=29) 14.9 ± 1.0 5.5 ± 0.5 p<0.001 p<0.001 Conclusions: An increase in the number of features of the metabolic syndrome leads to a progressive decrease in both large and small artery elasticity. 939-211 The Impact of Metabolic Syndrome and Coronary Artery Disease on Health Care Costs of Acute Cardiovascular Events Palacio Ana, Leonardo Tamariz, Bill West, Therese Burdey, Hermes Florez, University of Miami - Humana Health Services Research Center, Miami, FL Background: There is limited data examining the inﬂuence of acute cardiovascular (CV) events on health care costs. We evaluated the hypothesis that health care costs have a greater increase after an acute CV event in patients with metabolic syndrome (MS) particularly in those with history of coronary artery disease (CAD). Methods: We analyzed claims data from a large health insurance company and selected members between January 1, 2003 and May 31, 2004 with an ICD-9 code for acute myocardial infarction or cerebrovascular event. We compared total health care (medical and pharmacy) costs for the 6 months before and after these events. Members were classiﬁed as having MS equivalent if they had 3 or more of the following ICD-9 coded diagnosis: obesity, abnormal lipids, hypertension or diabetes. We also used ICD-9 codes to identify patients with a history of CAD. Results: We identiﬁed 39,873 members with an ICD-9 code for an acute CV event. The sample mean age was 68+/-13, consisted of 49% females and 57% were Medicare health plan participants. Using generalized linear models the overall mean difference in total health care costs between the post and pre event period adjusted for age, gender, region and plan type was USD 11184 (95% CI 10489-11878). These differences were greater in members with MS equivalent (USD 12551, 95 % CI 11580-13522) than in those without MS equivalent (USD 10377, 95% CI 9569-11185), even after adjusting for prior CAD. The presence of MS equivalent increased total health care costs in patients with acute myocardial infarction and/or cerebrovascular events (p <0.01). Conclusions: Acute CV events increase total health care costs, particularly in patients with the MS. Prevention strategies should be reinforced in patients at high risk for acute CV events, particularly in those with prior CAD and MS, to reduce the burden of these conditions and their associated health costs. 939-212 A Predisposition for the Metabolic Syndrome Increases Subclinical Inﬂammed Coronary Plaque Burden in Low Framingham Risk Women From a General Population Stefan Mohlenkamp, Axel Schmermund, Nils Lehmann, Susanne Moebus, Andreas Stang, Klaus Mann, Dietrich HW Grönemeyer, Rainer MM Seibel, Karl-Heinz Jöckel, Raimund Erbel, Heinz Nixdorf Recall Study Investigators, University Clinic Duisburg- Essen, Essen, Germany, University Witten-Herdecke, Bochum, Germany Background: Subjects at low Framingham (FH) risk are generally no candidates for aggressive risk intervention. Yet, published data suggest that subclincial plaque burden (i.e. coronary artery calcium, CAC) predicts events even in low risk subjects. hsCRP, indicating plaque inﬂammation, has been identiﬁed as a strong predictor of events in women. In an unselected population-based cohort we examined the extent to which a combined measure of inﬂammed plaque burden (based on CAC and hsCRP) impacts on risk stratiﬁcation in low risk women. Methods: Among 2147 women without known CAD aged 59±8 yrs a low FH risk (1.0mg/ dL excluded) was deﬁned to be elevated when I) CAC>100 and hsCRP>0.3mg/dl or II) CAC>400 and hsCRP>0.1mg/dl. Results: Mean FH risk in the low risk women was 5.3±2.4. A CAC between 100-400 was present in 7.8% and >400 in 2.9% of women. hsCRP was between 0.1-0.3 mg/dl in 36.3% and >0.3 mg/dl in 21.3% of women. Elevated CAC+hsCRP-values were found in 4.3% of women. Women with a low FH risk but elevated CAC+hsCRP-values, i.e. those that are candidates for risk intervention, were characterized by several risk factors, most of which contribute to the metabolic syndrome (Tab.1). Conclusion: The extent and inﬂammatory activity of subclinical CAD is underestimated in low risk women with predisposition for the metabolic syndrome using the FH risk score alone. In these women, measuring CAC and hsCRP may have a role in improved individual risk assessment. CAC + hsCRP in low FH risk (<10%/10yrs) women CAC + hsCRP not elevated (n=1536) elevated CAC + hsCRP (n=69) p-value age [yrs] 58±8 64±7 <0.0001 BMI [kg/m²] 27±5 29±6 <0.0001 RR syst [mmHg] 122±18 129±18 <0.001 Triglycerides [mg/dL] 114±56 140±69 <0.001 established Diabetes [%] 2.7 11.6 <0.0001 Glukose [mg/dL] 103±14 115±42 =0.003 HbA1c [%] 5.3±0.6 5.6±0.8 <0.001 FH risk 5.2±2.4 6.9±1.9 <0.0001 939-213 Current Trends in the Prevalence of Metabolic Syndrome Risk Factors Benjamin A. Steinberg, Philip O’Hagan, Philip Chadwell, Graham Turner, Christopher P. Cannon, Brigham & Women’s Hospital, Boston, MA, TNS Healthcare, Epsom, United Kingdom BACKGROUND: The recognition of the metabolic syndrome (Met Synd) in recent years has helped focus attention on this multifactorial epidemic. Few data are available on the prevalence of Met Synd, its change over time, or the current treatments used for these patients. METHODS: CardioMonitor is an annual sample of approximately 4600 ambulatory patients with cardiovascular disease (CVD) from 250 primary care physicians and 50 cardiologists, regionally representative. Extrapolation to the entire U.S. population was performed using weighting methodology based on each physician as representative of the physician population and each patient based on proportion of workload and frequency of consultation. A conservative estimate of the trends in Met Synd was evaluated using the NCEP deﬁnition; lab data were used where applicable, a BMI >30 kg/m2 was used to estimate obesity, and either a diagnosis of diabetes or in 2004 a physician’s diagnosis of impaired glucose tolerance was used to diagnosis elevated glucose. RESULTS: In 1998, 2001, and 2004, 61.4 million, 66.7 million, and 67.2 million patients were estimated to have CVD or CAD risk factors, respectively. Rates of hypertriglyceridemia over 150 mg/dL (45%, 45%, 28%), low HDL (33%, 31%, 31%), and hypertension (29%, 28%, 19%) all decreased over the observed time period, as statin usage for these patients increased from 37%, to 51%, to 52%. Despite these trends, the rates of Met Synd (≥3 of any of these) increased from 20%, to 22%, to 24% over the same period. This increase, therefore, was primarily driven by rates of obesity (30%, 35%, 48%) and impaired glucose tolerance (18%, 20%, 27%) over this period. CONCLUSION: Despite decreases in patients with hypertension, hypertriglyceridemia, and low HDL, the prevalence of Met Synd in the U.S. has increased steadily since 1998, driven by obesity and impaired glucose tolerance. Therefore, new medical treatments and/ or improved strategies of lifestyle modiﬁcation are urgently needed to reverse this trend. ACC_2006_8_VascularDisease.indd 312 1/4/06 5:21:03 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 313A Vascular D isease, H ypertension, and P revention ORAL CONTRIBUTIONS 801 Markers of Atherosclerosis and Cardiovascular Risk Monday, March 13, 2006, 7:00 a.m.-8:30 a.m. Georgia World Congress Center, Room B402 7:00 a.m. 801-3 Circulating Levels of Osteopontin Predicts Future Cardiac Events in Patients With Chronic Stable Angina Colomba Falcone, Enzo Emanuele, M. Paola Buzzi, Alessandra Repetto, Luca Ballerini, Silvia Salaro, Daniele Maniaci, Diego Geroldi, IRCCS Policlinico S. Matteo, Pavia, Italy, Interdipartimental Center for Research, University of Pavia, Pavia, Italy Background: Levels of the secreted glycophosphoprotein osteopontin have been associated with the presence and extent of coronary artery disease (CAD). The present study assessed the relationship between plasma osteopontin and prognosis in patients with chronic stable angina. Methods: Osteopontin was measured in baseline plasma samples from 799 patients with stable angina pectoris and angiographically documented CAD. Participants were prospectively followed-up for a median of 2.7 years (maximum 4.1 years). The primary study endpoint was the composite of non-fatal myocardial infarction and death from cardiovascular causes. Results: Sixty-nine patients (8.6 percent) reached the study endpoint during follow-up. Median baseline osteopontin concentrations in plasma were signiﬁcantly higher (P < 0.001) in the patients who developed an adverse outcome (343 ng/mL) in comparison with event- free individuals (248 ng/mL). After adjustment for most potential confounders, the hazard ratio for future cardiovascular events for the patients with osteopontin levels in the fourth quartile as compared with those in the ﬁrst quartile was 2.06 (95% conﬁdence interval: 1.45-2.93, P < 0.001). Signiﬁcant correlations were found between baseline circulating osteopontin and age (r = 0.14, P < 0.001), C-Reactive Protein levels (r = 0.10, P = 0.005), triglycerides concentrations (r = 0.09, p = 0.02) and the number of signiﬁcantly diseased vessels (r = 0.18, P < 0.001). Notably, patients receiving statins had lower levels of osteopontin as compared with patients who did not take these drugs (median 251 ng/mL vs. 329 ng/mL, respectively, P < 0.001). When variables with a P value of < 0.20 at univariate analysis were entered into a multiple regression model, the treatment with statins (β = -0.18, P < 0.001), the number of diseased vessels (β = 0.17, P < 0.001), as well as age (β = 0.14, P < 0.001) were independent predictors of plasma osteopontin levels. Conclusions: Baseline levels of osteopontin are an independent predictor of future adverse cardiac events in patients with chronic stable angina pectoris, and may be useful for risk stratiﬁcation. 7:15 a.m. 801-4 Osteoprotegerin as a Novel Biomarker of Atherosclerosis: Independent Association With Coronary Artery Calcium in the Dallas Heart Study Moeen Abedin, Torbjorn Omland, Amit Khera, Pal Aukrust, Thor Ueland, Tulika Jain, Sabina Murphy, Ugis Gruntsmannis, Darren McGuire, James deLemos, Donald W. Reynolds Cardiovascular Research Center at U.T. Southwestern, Dallas, TX, University of Oslo, Oslo, Norway Background: Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor superfamily, is a potent inhibitor of osteoclastogenesis and regulator of bone metabolism. The relationship of OPG to vascular calciﬁcation is unclear. Methods: Plasma OPG levels were measured in 3386 subjects in the Dallas Heart Study, a multiethnic, population-based probability sample of adults age 30-65. Coronary artery calcium (CAC) was measured by electron beam computed tomography with prevalent CAC deﬁned by Agatston score > 10. Mutivariable logistic regression was used to assess associations between OPG, cardiovascular risk factors, and CAC. Results: Advanced age, female sex, black race, smoking, personal and family history of coronary artery disease (CAD), diabetes, hyperlipidemia, and CAC were signiﬁcantly associated with higher plasma OPG levels (p < 0.01) in univariable analyses. Prevalence of CAC increased across OPG quartiles (15.5%, 17.1%, 22.6% and 30.2%, p<0.001; Figure). Compared with the 1st quartile, OPG level in the 4th quartile was independently associated with CAC (RR 1.39, 95% CI 1.01 - 1.93) after adjustment for age, sex, smoking, diabetes, hyperlipidemia and family history of premature CAD. Conclusions: Plasma OPG is independently associated with CAC, suggesting it may be a novel biomarker for atherosclerosis in humans. The roles of OPG in atherogenesis and cardiovascular events require further study. 7:30 a.m. 801-5 Aortic Pulse Wave Velocity Is Associated With Presence and Quantity of Coronary Artery Calcium: A Community-Based Study Iftikhar J. Kullo, Lawrence F. Bielak, Stephen T. Turner, Patrick F. Sheedy, II, Patricia A. Peyser, Mayo Clinic, Rochester, MN, University of Michigan, Ann Arbor, MI Background: We investigated the relationship of aortic pulse wave velocity (aPWV), a measure of central arterial stiffness, to the presence and quantity of coronary artery calcium (CAC) in a community-based sample of adults without prior history of heart attack or stroke. Methods: Participants (n = 401) had a mean age of 59.8 years and 53% were men. ECG-gated waveforms of the right carotid and right femoral artery were obtained by applanation tonometry and aPWV was calculated using established methods. CAC was measured non-invasively by electron beam computed tomography and CAC score was calculated using the method of Agatston. Multivariable logistic, ordinal, and linear regression models were employed to identify independent predictors of the presence, grade, and quantity of CAC. Results: aPWV was signiﬁcantly correlated with log (CAC score +1) (r = 0.41; P < 0.0001) and pulse pressure (r = 0.47, P < 0.0001). In multivariable logistic regression analyses, aPWV was associated with presence of CAC (P = 0.014) after adjustment for age, sex, total cholesterol, HDL cholesterol, diabetes, history of smoking, systolic blood pressure, body mass index, and use of statins and hypertension medications. In separate multivariable ordinal logistic and linear regression analyses, aPWV was signiﬁcantly associated with higher grade of CAC (P = 0.030) and with log (CAC score +1) (P <0.0001) after adjustment for the covariates enumerated above. aPWV remained signiﬁcantly associated with both the presence and quantity of CAC even after additional adjustment for pulse pressure. Conclusions: aPWV, a measure of arterial stiffness, is related to subclinical coronary atherosclerotic burden independent of conventional risk factors including indices of blood pressure and may be a marker of cardiovascular risk of asymptomatic individuals. 7:45 a.m. 801-6 Long-Term Association of Brachial Artery Flow- mediated Vasodilation and Cardiovascular Events in Middle-Aged Subjects With no Apparent Heart Disease Michael Shechter, Assaf Issachar, Ibrahim Marai, Nira Koren Morag, Dov Freimark, Shlomi Matetzky, Vitali Usmanov, Stanislava Gilman, Micha S. Feinberg, Heart Institute, Sheba Medical Center, Tel Hashomer, Israel Background: Endothelial dysfunction is considered as an important factor in atherosclerosis and has prognostic value. The purpose of this study was to ﬁnd out the long-term association of peripheral vascular endothelial function and clinical outcome in healthy subjects with no apparent heart disease. Methods and Results: We prospectively assessed ﬂow-mediated dilation (FMD) in 435 consecutive healthy subjects without known coronary artery disease (CAD), 270 (62%) men, mean age 54±12 (range 17-81) years and body mass index 28±4 kg/m2. After an overnight fast and discontinuation of all medications for ≥ 12 hours, percent improvement in endothelium-dependent brachial artery ﬂow-mediated dilation (%FMD) and endothelium- independent nitroglycerin (%NTG)-mediated vasodilatation were assessed using high resolution (15 MHz) ultrasound. Subjects were divided into 2 groups: below (n=221) and above (n=214) the median %FMD of 10.7%. The 2 groups were comparable in regard to CAD risk factors, lipid panel, fasting glucose, hs-CRP, and concomitant medications. Subjects underwent clinical follow-up for a mean of 15±2 months. The composite cardiovascular endpoints (including all-cause mortality, non-fatal myocardial infarction, hospitalization for heart failure or angina pectoris, stroke, coronary artery bypass grafting and percutaneus coronary interventions) were signiﬁcantly more common in subjects with %FMD below than above the median of 10.7% (11.8% vs 4.7%, p=0.007, respectively). Univariate analysis demonstrated that the median %FMD signiﬁcantly predicted cardiovascular events with an odds ratio (OR) of 2.78 and 95% CI (1.35 to 5.71) (p=0.003). After multivariate analysis that included conventional risk factors for atherosclerosis, median %FMD was the best independent predictor of long-term cardiovascular adverse events with an OR of 2.93 and 95% CI (1.285 to 6.688) (p=0.011). ACC_2006_8_VascularDisease.indd 313 1/4/06 5:21:03 PM 314A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n Conclusions: Brachial artery median %FMD independently predict long-term adverse cardiovascular events in healthy subjects in addition to that derived from traditional risk factor assessment in humans. Larger long-term studies are required to determine the clinical value of these results. 8:00 a.m. 801-7 Vascular and Biochemical Markers of Cardiovascular Risk in Healthy Subjects With the Metabolic Syndrome Narbeh Melikian, Philip Chowienczyk, Philip A. MacCarthy, Ian L. Williams, Stephen B. Wheatcroft, Roy Sherwood, Ajay M. Shah, Mark T. Kearney, Cardiovascular Division, King’s College School of Medicine at Guy’s King’s and St Thomas’ Hospitals, London, United Kingdom, King’s College Hospital, London, United Kingdom Background: C-reactive protein (CRP) is an independent marker of future cardiovascular (CVS) risk. CRP levels are higher in asymptomatic subjects with metabolic syndrome [(MS) deﬁned by ATP-III criteria] and correlate positively with the number of ATP-III diagnostic criteria present. The association between alternative markers of CVS risk [vascular function, tumour necrosis factor � (TNF), interleukin6 (IL6)] in the context of the MS is unclear. We have investigated this association. Methods: 100 [61 male; mean age (years±SEM) with MS (n=24) 36±2, without MS (n=76) 33±1; p=NS] asymptomatic, non-diabetic, non-smokers were screened for MS and divided into two groups depending on presence/absence of MS. TNF, IL-6 were measured by ELISA. High-resolution brachial artery ultrasonographic studies were performed to assess endothelium-dependent [ﬂow-mediated dilatation (FMD)] and -independent [glyceryl-trinitrate induced] vascular responses. Results: Subjects with MS had impaired FMD (p<0.001) and higher TNF (p<0.001), IL-6 (p<0.001) levels in comparison to subjects without MS. There was no difference in endothelium-independent vascular response. Brachial artery diameter did not correlate with FMD (r2=0.01, p=NS), conﬁrming that arterial size did not inﬂuence endothelial reactivity. Oneway analysis of variance showed a signiﬁcant negative linear trend between mean FMD (F=21.89, p<0.001) and a positive trend between logIL6 (F=28.17, p<0.001), logTNF (F=12.94, p=0.001) and number of ATP-III metabolic diagnostic criteria present. In a stepwise multivariate regression model presence/absence of MS was the only independent determinant of FMD [B=2.38, SE(B)=0.94, p=0.01, CI=1.71-67.49] with age, gender, LDL, CRP, IL6 and TNF having no independent inﬂuence. Conclusions: Asymptomatic subjects with MS had greater endothelium-dependent vascular dysfunction and higher levels of TNF and IL-6. All three variables correlated with the number of ATP-III metabolic diagnostic criteria present. MS was the only independent determinant of endothelial function 8:15 a.m. 801-8 Plasma Concentration of Lipoprotein(a) and the Risk of Future Cardiovascular Disease in Women Jacqueline Suk Danik, Nader Rifai, Julie E. Buring, Paul M. Ridker, Brigham and Women’s Hospital, Boston, MA, Children’s Hospital, Harvard Medical School, Boston, MA BACKGROUND: Lipoprotein(a) (Lp(a)), a lipoprotein with sequence homology to plasminogen, may have ﬁbrin-binding qualities. Elevated Lp(a) has been associated with premature coronary disease but debate exists as to whether it is a risk factor in women. This study sought to assess the risk of future cardiovascular events associated with baseline Lp(a) levels in women. METHODS: Lp(a) was measured in baseline plasma samples of 27,792 initially healthy women in the Women’s Health Study and followed prospectively for 10 years for the primary endpoint of cardiovascular disease. RESULTS: Median Lp(a) concentrations (12.60 vs. 10.60 mg/dL, P<0.0001) and overall Lp(a) distributions differed at baseline in women who did and did not develop cardiovascular disease. In analyses controlling for age, smoking, blood pressure, obesity, diabetes, and hormone use, women in the ﬁfth quintile of Lp(a) values (median value 65.5 mg/dL) were 1.6 times more likely to develop cardiovascular disease than women in the ﬁrst quintile (median value 1.9 mg/dL, P<0.0001). This risk increase, however, was due almost entirely to a threshold effect among those with the very highest Lp(a) levels; the adjusted relative risk associated with baseline Lp(a) levels exceeding the 95th percentile of the control distribution was 2.02 (95%CI 1.62 to 2.52) with almost no risk gradient at lower levels. CONCLUSIONS: In this study of initially healthy women, very high levels of Lp(a) were associated with an increased risk of cardiovascular disease. ORAL CONTRIBUTIONS 802 Peripheral Arterial and Aortic Disease Monday, March 13, 2006, 7:00 a.m.-8:30 a.m. Georgia World Congress Center, Room B206 7:00 a.m. 802-3 Expression and Function of Toll-like Receptors in Different Vascular Beds: Towards Understanding Target Tissue Susceptibility in Vascular Inﬂammation Olga Pryshchep, Wei Ma-Krupa, Kazunori Shimada, Augusto Vaglio, Jorg J. Goronzy, Cornelia M. Weyand, Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA Background: Toll-like receptors (TLR) are a family of pattern-recognition molecules that detect “danger” and initiate immune responses. TLR are typically expressed on dendritic cells (DC), but low levels are found on vascular smooth muscle and endothelial cells. We hypothesize that medium-sized arteries in different vascular territories express distinct TLR proﬁles and TLR patterns are a risk factor for inﬂammatory vasculopathies, such as arteritis or atherosclerosis. Methods: Human medium-sized and large arteries were collected from 6 vascular beds (temporal, carotid, subclavian, mesenteric, iliac and thoracic aorta) of 21 donors (mean age 65 years). All samples were free of atherosclerotic plaque and inﬂammatory inﬁltrates by histology. mRNA expression for TLR 1-9 and the DC marker CD11c was quantiﬁed by real- time PCR. Distribution of vascular DC was evaluated by immunohistochemistry. Functional relevance of TLR expression was tested by implanting human arteries into SCID mice, injecting the TLR ligand LPS (3mg/mouse), and adoptively transferring 5x106 human T cells. Vascular inﬂammation was assessed by analysis of explanted artery grafts. Results: LPS stimulation of human artery-SCID chimeras (n=8) induced inﬁltration of adoptively transferred T cells into the media demonstrating a central role for TLR ligation in vascular inﬂammation. Transcripts for all TLRs except TLR8 were present in all arteries; however, each vascular territory expressed a unique proﬁle. Sharing of TLR expression patterns was seen for carotid and iliac arteries. Temporal arteries were distinct from other vessels and characterized by high expression of TLR2 and TLR8. The aortic wall expressed the lowest transcript levels. The load of DC varied in different arteries, and iliac arteries displayed the highest density. Conclusions: Arteries resemble lymphoid tissues in that they express high levels of TLR 1-9. TLR ligation initiates vessel wall inﬁltration by T lymphocytes and may play a critical role in vascular inﬂammation. Different vascular beds have distinct TLR proﬁles, possibly reﬂecting the susceptibility of particular artery types for certain inﬂammatory vasculopathies. 7:15 a.m. 802-4 Proteomic Proﬁling Reveals that Plasma Beta 2- Microglobulin is a Marker for Peripheral Arterial Disease Eiichiro Kimura, Nandini Nair, Randall K. Harada, Balasubramanian Narasimhan, Xiao- Ying Meng, Fujun Zhang, Eric Fung, John P. Cooke, Stanford University, Stanford, CA, Ciphergen Biosystems, Fremont, CA Background: Peripheral arterial disease (PAD) is under-diagnosed and under-treated. Towards the development of new clinical markers for PAD, we aimed to utilize a high- throughput proteomics approach to identify plasma proteins that are differentially expressed in patients with PAD. Methods: Plasma samples were collected before (baseline), immediately after, and 2 hours after an exercise treadmill test (Skinner-Gardner protocol), from PAD patients (n = 45) and control subjects without PAD (n = 43). PAD was deﬁned as a resting ankle- brachial index < 0.9. Plasma samples were fractionated using a stepwise decreasing pH gradient followed by an organic solvent elution. The fractions were applied to ProteinChip® arrays and analyzed using SELDI-TOF mass spectrometry. Differences in peak-intensities between PAD and control groups were evaluated using the Statistical Analysis of Microarrays (SAM) software. Results: 1,619 peaks were measured from each of 6 fractions per patient-sample. SAM revealed signiﬁcant differences among a subset of proteins between PAD and control groups. Of these proteins, one with a molecular weight of 12 kDa showed a highly signiﬁcant difference in mean peak-intensity at baseline between the two groups (PAD, 13.88 ± 1.61 vs control, 7.53 ± 0.49, p < 0.001). Furthermore, peak-intensity levels of the 12 kDa protein negatively correlated with ankle-brachial indices (a surrogate measure of PAD severity; rs = -0.401, p < 0.01). The biochemical properties of this potential marker as determined by SELDI-TOF were most consistent with beta 2-microglobulin. The identity of the protein was conﬁrmed by immunoafﬁnity studies and western blot analyses. Conclusions: Analyses of a large set of proteomic proﬁles from patients with PAD and matched controls revealed that plasma beta 2-microglobulin was elevated in patients with PAD, and its levels inversely correlated with ankle-brachial indices. The mechanism by which beta 2-microglobulin is elevated in PAD and its possible pathophysiological role are under investigation. ACC_2006_8_VascularDisease.indd 314 1/4/06 5:21:04 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 315A Vascular D isease, H ypertension, and P revention 7:30 a.m. 802-5 The Inﬂection Point Is Not a Reliable Method for the Determination of the Augmentation Index Ashraf W. Khir, Alun D. Hughes, Kim H. Parker, Brunel University, Uxbridge, United Kingdom, Imperial College London, London, United Kingdom Background: Augmentation index (AIx) is widely used as a measure of wave reﬂection, and the validity of the technique depends on the ability to ascertain the arrival time of reﬂected waves (TRW). This study compares the determination of AIx using the inﬂection point (Ip) method and wave intensity analysis (WIA). Methods: In 11 anaesthetised dogs, total occlusions of the aorta were produced at 3 sites (thoracic, diaphragm, abdominal), and at the left iliac artery. Pressure and ﬂow in the ascending aorta were measured before and during the occlusion and wave speed was determined using the PU-loop method. The Ip indicating TRW was determined as the zero crossing of the 4th derivative of the pressure waveform. TRW was also determined as the onset of the backward wave using wave intensity analysis. AIx was determined as the ratio of the difference between systolic pressure and pressure at TRW to the difference between systolic and diastolic pressure. Results: During control, TRW determined using the 4 th derivative and WIA was (0.05±0.005s vs. 0.04±0.003s; p<0.05) and the corresponding AIx was (47±2 vs. 72±7; p<0.05). During thoracic and diaphragm occlusions, AIx determined using the 4th derivative and WIA was (45±3 vs. 84±8; p<0.05) and (49±4 vs. 80±7; p<0.05) respectively. AIx estimated using the 4th derivative was not signiﬁcantly affected by any of the occlusions, where it was only signiﬁcantly affected during thoracic and diaphragm occlusions, when estimated using WIA. Conclusion: The inﬂection point is not an accurate measure for determining TRW, when the reﬂection and measurement sites are nearing close proximity. This can result in signiﬁcant errors in the estimation of AIx. The pressure-ﬂow relationship in the wave intensity analysis is more reliable in detecting TRW and AIx, than the Ip method using only the pressure waveform. 7:45 a.m. 802-6 Contrast Ultrasound Perfusion Imaging: The Beginning of a New Era in the Diagnostic of Peripheral Artery Disease? Qian Zhou, Daniel Duerschmied, Dorothee Harder, Elisabeth Rink, Christoph Bode, Christoph Hehrlein, University Hospital of Freiburg, Dep. of Cardiology and Angiology, Freiburg, Germany Background: Atherosclerosis is the leading cause of peripheral arterial disease (PAD) and is associated with an increased rate of cardiovascular mortality. Recent investigations have lead to the development of a novel method allowing the direct detection of muscle perfusion in the lower limb by using contrast ultrasound perfusion imaging (CUPI) in PAD patients. Methods: The current study compared differences of wash-in time in 20 non-diabetic PAD patients (Fontaine IIa/b) to 33 control subjects. For CUPI, 4.8 ml SonoVueTM injection was injected intravenously before and after calf exercise. Distribution of the contrast medium was analysed by using the time intensity curve - analysis provided by GE Healthcare Technologies, Ultrasound. All statistical tests were two-sided and Mann-Whitney U-Test was used to compare baseline variables between the study groups. Statistical analysis was performed using the SPSS-Software Version 13.0, LEAD Technologies Inc., Chicago, USA. Results: Time to peak intensity (TTP) was deﬁned as duration of the contrast wash-in curve. The median TTP measured after 10 minutes at rest in a supine position was 27s {15.4-61.0} in control subjects and 47.5s {19.0-80.0} in PAD patients. After calf exercise control subjects show a median TTP of 16s {8.0-33.0} versus 28s {12.6-48.0} in PAD patients. The difference between these two groups was signiﬁcant in both examinations (Mann-Whitney, p < 0.001). Partial correlation between ankle-brachial-index (ABI) and TTP did not show any signiﬁcance before exercise (r=0.09) or after exercise (r=-0.35). Conclusion: The use of contrast ultrasound perfusion imaging CUPI is highly sensitive and speciﬁc to detect peripheral arterial disease. Partial correlation analysis has not shown any signiﬁcant correlation between TTP and ABI, indicating that CUPI integrates information about the muscle perfusion including the microcirculation. 8:00 a.m. 802-7 Partial False Lumen Thrombosis as a Predictor of Mortality in Patients with Type B Acute Aortic Dissection: Insights from The International Registry of Acute Aortic Dissection (IRAD) Thomas T. Tsai, Arturo Evangelista, Christoph Nienaber, Truls Myrmel, Udo Sechtem, Jeanna V. Cooper, Toru Suzuki, Rosella Fattori, Alessandro Distante, Thor Sundt, Joshua Beckman, Jim Januzzi, Eric Isselbacher, Kim Eagle, University of Michigan, Ann Arbor, MI Background: Patency or thrombosis of the false lumen is predictive of long-term mortality in patients with type B acute aortic dissection (TB-AAD). The signiﬁcance of partial false lumen thrombosis has not been well studied. Methods: We examined 152 consecutive patients with TB-AAD enrolled in IRAD from 1996 to 2003 who were discharged alive and had follow-up data as well as imaging evaluation of the false lumen during the index hospitalization. Bivariate and multivariate analyses were performed to determine the relationship between false lumen status and long-term mortality. Results: Median follow-up was 344 days. A patent false lumen was seen in 75 (49%) patients, a completely thrombosed false lumen in 18 (12%), and a partially thrombosed false lumen in 59 (39%). Unadjusted analyses demonstrated higher mortality in patients with partial false lumen thrombosis and lowest mortality in patients with complete false lumen thrombosis (22.8% vs 8.0% vs 5.9%, p=0.029) (Figure). After multivariable adjustment for age, gender, and treatment by medical or surgical therapy, partial false lumen thrombosis remained an independent predictor of long-term mortality (OR, 3.12 95% CI, 1.12-8.70; p=0.029). Conclusions: Partial false lumen thrombosis may portend an even greater risk of mortality than a completely thrombosed or patent false lumen. Potential mechanisms include increased transaortic pressure in the false lumen due to a patent entry tear and a distal thrombosis occluding blood ﬂow back to the true lumen. 8:15 a.m. 802-8 First Report of the CASES-PMS Study: Patient Demographics and 30-Day Major Adverse Events for the Cordis PRECISE™ Nitinol Stent and Angioguard™ XP Emboli Capture Guidewire Condition of Approval Surveillance Study Theodore Schreiber, Sidney Cohen, Douglas Massop, Vinay Kumar, Thomas Davis, Stephen Ramee, Cordis, Warren, NJ Background: CASES-PMS is a multicenter, prospective, single arm, open-label study to assess safety & efﬁcacy outcomes of stenting with distal emboli protection (CAS) in the treatment of obstructive carotid artery disease. The study was undertaken as a condition of approval surveillance study of the Cordis PRECISE™ Nitinol Stent & Angioguard™ XP Emboli Capture Guidewire. The study objective is to demonstrate that the 30-day Major Adverse Event (MAE) rate is comparable to that of the pivotal SAPPHIRE trial. Methods: The study enrolled high surgical-risk patients with de novo atherosclerotic or post-endarterectomy restenotic obstructive lesions in native carotid arteries. Inclusion & exclusion criteria match those of the SAPPHIRE trial. Clinical follow-up is conducted at 30-days & 1-year post-procedure. The 30 day assessment includes a neurological examination by a neurologist & an evaluation of adverse events. At 1-year post-procedure an evaluation for adverse events is performed. The 1° endpoint is a 30-day composite of MAE including death, any stroke, &/or myocardial infarction. Results: 1500 patients were enrolled at 72 sites from September 24, 2004 through October 7, 2005. Patient demographics are detailed below: Baseline Characteristics CASES 95% CI Age (mean +/- SD (N)) 74.9+/- 9.5 [74.03, 75.82] Number of Men 61.70% [56.9%, 66.4%] History of Hypertension 89.60% [86.3%, 92.3%] History of MI 36.10% [31.5%, 40.9%] History of Smoking 66.50% [61.8%, 71.0%] Prior Coronary Revascularization 42,5% [37.7%, 47.4%] Diabetes Mellitus 37.20% [32.7%, 42.0%] History of TIA 31.30% [26.9%, 35.9%] History of Stroke 30.70% [26.4%, 35.3%] Prior carotid endarterectomy 28.70% [24.5%, 33.2%] Symptomatic 28.70% [24.5%, 33.2%] Abnormal stress test 10.10% [7.4%, 13.3%] Unstable Angina 9.20% [6.7%, 12.3%] CHF +/- severe left ventricular dysfxn 17.20% [13.8%, 21.1%] Severe pulmonary disease 12.20% [9.2%, 15.6%] Age >80 years as a single risk factor 38.20% [33.6%, 42.9%] Previous CEA with recurrent stenosis 23.90% [20.0%, 28.8%] Conclusions: 30 day Major Adverse Event outcomes will be presented on the entire CASES-PMS cohort. ACC_2006_8_VascularDisease.indd 315 1/4/06 5:21:04 PM 316A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n ORAL CONTRIBUTIONS 808 LDL, VLDL, HDL: All Are Swell Monday, March 13, 2006, 7:00 a.m.-8:30 a.m. Georgia World Congress Center Room, B405 7:00 a.m. 808-3 Intensive Lipid Lowering With Atorvastatin Is Associated With a Signiﬁcant Improvement in Renal Function: The Treating to New Targets (TNT) Study James Shepherd, Nanette K. Wenger, The TNT Steering Committee and Investigators, University of Glasgow, Glasgow, United Kingdom, Emory University School of Medicine, Atlanta, GA Background: Data suggest that atorvastatin may have nephroprotective effects, possibly as a result of direct vascular effects. The TNT study showed that intensive lipid-lowering therapy with atorvastatin (ATV) 80 mg/day provides signiﬁcant clinical beneﬁt beyond that afforded by treatment with ATV 10 mg/day in patients with stable CHD. The current post hoc analysis of the TNT study investigated how intensive lipid lowering with ATV 80 mg affected renal function compared with ATV 10 mg in this population. Methods: 10,001 patients with clinically evident CHD, with LDL-C levels of <130 mg/dL (3.4 mmol/L) on ATV 10 mg/day were randomized to double-blind therapy with either ATV 10 mg/day or 80 mg/day. Patients were followed for a median of 4.9 years. Creatinine clearance (CrCl), calculated from the Cockroft-Gault formula, was compared at baseline (following 8 weeks’ ATV 10 mg/day) and at the end of follow-up using a last observation carried forward analysis in the 7965 patients with a baseline and at least one post- baseline creatinine measurement. Results: Mean calculated CrCl was 78.8 and 77.5 ml/min at baseline in the ATV 10 mg and 80 mg groups, respectively, with a mean difference between the groups of 1.1 ml/min (95% CI = 0.31, 1.89; p=0.006). At the end of follow-up, mean CrCl was increased by 1.1 ml/min in the ATV 10 mg group and by 2.7 ml/min in the ATV 80 mg group. The difference between treatment groups in mean change (1.6 ml/min; 95% CI = 1.06, 2.05) and mean percent change from baseline (2.1%; 95% CI = 1.49, 2.74) were both highly signiﬁcant (p<0.0001). In the ATV 80 mg arm, CrCl improved to >60 ml/min in signiﬁcantly more patients and declined to <60 ml/min in signiﬁcantly fewer patients than in the ATV 10 mg arm. There were no interactions with center, race, age, or gender. Blood pressure control was similar between the 2 groups. Both treatments were well tolerated. Conclusions: Both ATV 10 mg and 80 mg blunted the expected decline in renal function over the 5 years of the TNT study. In addition to improved lipid control and further reductions in major cardiovascular events, intensive treatment with ATV 80 mg resulted in a signiﬁcant improvement in renal function over that of ATV 10 mg in patients with stable CHD. 7:15 a.m. 808-4 Impact of Low High-density Lipoproteins on In-Hospital Events and Twelve-month Clinical Outcomes in Patients With Acute Coronary Syndrome Treated With Drug- eluting Stent Implantation Roswitha M. Wolfram, Zhenyi Xue, Natalie Gevorkian, Augusto D. Pichard, Lowell Satler, Kenneth M. Kent, Ron Waksman, Bryan H. Brewer, Jr., Washington Hospital Center, Washington, DC Background: High-density lipoprotein cholesterol (HDL-C) is known to have protective cardiovascular effects. We aimed to investigate the impact of HDL-C on the outcomes of patients undergoing drug-eluting stent (DES) implantation for acute coronary syndrome (ACS). Methods: We analyzed data of 550 consecutive patients with low HDL-C (male: HDL-C <40mg/dl, female: HDL-C <45mg/dl, mean: 32±7 mg/dl) treated with DES implantation and 482 consecutive patients with high HDL-C (male: HDL-C >40mg/dl, female: HDL- C >45mg/dl,mean: 55±19 mg/dl). The assessed end points, death, non-fatal myocardial infarction (MI), target lesion revascularization (TLR), and a composite of major adverse cardiac events (MACE) were then compared between groups. Results: Levels of low-density lipoprotein cholesterol (LDL-C) and statin treatment (98% in both groups) were comparable. Low HDL-C patients had more diabetes, higher triglyceride levels, a higher BMI, and lower total cholesterol levels. Incidence of mortality and TLR-MACE at 30 days was higher in the low- versus the high HDL-C group. From 30 days to 1 year, more deaths occurred in the low HDL-C group as did TLR-MACE (Table). Multivariate analysis revealed low HDL-C (HR=2.61, 95%CI: 1.33 - 5.12) to be a key predictor of TLR- MACE and death (HR=0.30, 95%CI: 0.10 - 0.87) at 1 year. Conclusion: Patients with low HDL-C are at higher risk for PCI complications. Additional strategies to increase HDL-C should be evaluated in high-risk patients with ACS undergoing DES implantation. Adverse Events 0 to 30 Days >30 Days to 1 Year % Event % Event High HDL Low HDL RR (95% CI) High HDL Low HDL RR (95% CI) Death 0 3.0 - 3.8 11.3 0.33 (0.11 - 0.98) Q-wave MI 0.3 0.50 0.55 (0.05 - 6.02) 3.8 6.7 0.57 (0.18 - 1.83) TLR-MACE 0.3 3.2 0.09 (0.01 - 0.66) 12.0 26.7 0.45 (0.25 - 0.81) Late thrombosis - - - 0.6 0 - 7:30 a.m. 808-5 Effects of Ezetimibe/Simvastatin Compared to Simvastatin Monotherapy in Reducing C-Reactive Protein and Low Density Lipoprotein-Cholesterol Christie M. Ballantyne, Paul Ridker, Thomas Pearson, Enrico Veltri, Yale B. Mitchel, Christine M. McCrary Sisk, Arvind K. Shah, Darbie L. Maccubbin, Baylor College of Medicine, Houston, TX, Brigham and Women’s Hospital, Boston, MA Background: In addition to lowering cholesterol, statins reduce C-reactive protein (CRP) and may play a direct role in modifying atherosclerosis. Ezetimibe/simvastatin (EZE/SIM) reduces LDL-C to a greater extent than SIM alone. This study evaluated the CRP lowering effects of both agents. Methods: This post hoc analysis pooled data from 3 similar randomized, placebo (Pbo) controlled, double blind studies. After a 6 to 8 wk washout and 4 wk diet/Pbo run in, 3083 hypercholesterolemic patients (LDL-C: 145 - 250 mg/dL; TG ≤ 350 mg/dL) were randomized equally to Pbo, EZE 10 mg, EZE/SIM (10/10, 10/20, 10/40, 10/80 mg), or SIM (10, 20, 40, 80 mg) for 12 wks. Changes in CRP and LDL-C and the percentage of patients achieving deﬁned single and dual LDL-C (<70 and <100 mg/dL) and CRP (<1 and <2 g/L) levels were examined across individual and pooled treatment groups. Results: EZE alone did not signiﬁcantly reduce CRP vs Pbo. Pooled EZE/SIM produced signiﬁcantly greater CRP and LDL-C reductions vs pooled SIM alone (Table). Signiﬁcantly more patients in the pooled groups achieved single LDL-C and CRP, and dual LDL-C/ CRP levels with EZE/SIM vs SIM alone (Table). The enhanced CRP lowering effect was similar among subgroups based on age (<65 vs ≥65 years), gender, body mass index (<30 vs ≥30 kg/m2), coronary heart disease, diabetes and metabolic syndrome status. Conclusions: Although EZE alone did not signiﬁcantly reduce CRP vs Pbo, EZE/SIM provided additional incremental CRP and LDL-C lowering beyond that achieved with SIM alone. 7:45 a.m. 808-6 Triple-Therapy with a Statin, Fibrate and Ezetimibe Safely Allows More Diabetic Patients with Mixed Dyslipidemias to Reach NCEP Guidelines: An Analysis of The DIACOR Study Robert R. Pearson, Heidi Thomas, Jonathan R. Jensen, Benjamin D. Horne, Donald L. Lappé, Jeffrey L. Anderson, Joseph B. Muhlestein, LDS Hospital, Salt Lake City, UT, University of Utah, Salt Lake City, UT Background: Diabetes (DM), a strong risk factor for cardiovascular disease (CVD), is often characterized by mixed dyslipidemia (MD). Many DM patients (pts) are unable to achieve optimal lipid parameters as deﬁned by the NCEP III guidelines with mono or dual lipid- lowering drug therapies alone. Little information exists regarding the safety and efﬁcacy of triple-therapy with 20 mg simvastatin (S), 160 mg fenoﬁbrate (F) and 10 mg ezetimibe (E). Methods: The DIACOR study enrolled pts with type II DM, MD, and no CVD. After 12 weeks of randomized therapy of F, S, or their combination (C), all patients received 9 months of C. Pts who still had a LDL >100 mg/dL or triglycerides >150 mg/dL on C therapy were then randomized in a double-blinded fashion to receive either: C and E (CE) or C and placebo (CP). Pts were then followed for 6 weeks post randomization for safety (rhabdomyolysis, clinical myopathy [CK>10 ULN], persistent myalgias, adverse liver- related event [consecutive elevated AST or ALT (>3xULN)], or any other patient-reported adverse event), efﬁcacy, and NCEP goals. Results: A total of 37 pts have been randomized, average age 59.8 ±10, with 35% female. For CE vs. CP, 23.5% vs. 0% of the pts met all 3 NCEP goals, 76.5% vs. 80% met 1 or 2 goals, and 0% vs. 20% met no goals. The likelihood of meeting all three NCEP goals was signiﬁcantly increased in the CE group (p=0.006) vs. CP. In CE, there was a signiﬁcant incremental reduction from baseline to 6 weeks in total cholesterol (16.0%, p<0.0001), LDL (25.2%, p<0.0001), and VLDL (14.0%, p=0.1). There were no serious drug-related clinical adverse events in either arm of the study. Conclusion: DM pts on triple therapy were signiﬁcantly more likely to achieve all 3 NCEP III goals than double therapy. Additionally, triple therapy was safe and well tolerated with no serious adverse events, such as rhabdomyolysis, myalgias or hepatic injuries. Triple therapy is an appealing new approach in selected DM pts not at NCEP III goals and should be further evaluated. 8:00 a.m. 808-7 The Impact of Over-the-Counter Simvastatin on the Number of Statin Prescriptions in the United Kingdom: A View from the General Practice Research Database Kristian B. Filion, Joseph A. Delaney, James M. Brophy, Pierre Ernst, Samy Suissa, Royal Victoria Hospital, Montreal, PQ, Canada Background: The United Kingdom (UK) government changed the prescription policy of statins, making low-dose simvastatin (10 mg) available as an over-the-counter (OTC) drug. ACC_2006_8_VascularDisease.indd 316 1/4/06 5:21:05 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 317A Vascular D isease, H ypertension, and P revention To our knowledge, this report is the ﬁrst assessment of the impact of this policy change. Methods: We examined all statin prescriptions in the General Practice Research Database (GPRD) from the ﬁrst quarter of 2001 to the ﬁrst quarter of 2005. The GPRD is a well-validated database of approximately 5 million patients that contains a variety of medical information including prescriptions. We used linear regression to determine the effect of the policy change on the number of statin prescriptions over time. Results: Our investigation of the number of statin prescriptions in the GPRD indicates that the volume of prescription statins fell for the ﬁrst time in the ﬁrst quarter of 2005 after several years of increasing use. Importantly, this observed decrease in statin prescriptions was not restricted to prescriptions of 10 mg statins and was also observed for prescriptions of ≥ 20 mg statins. The regression model estimated that, since the beginning of 2001, the number of statin prescriptions written for patients in the GPRD has increased by approximately 14,900 prescriptions per quarter. However, there was a highly statistically signiﬁcant deﬁcit of 8,500 prescriptions per quarter in the four quarters that we observed post-policy change (p=0.004). Assuming the underlying linear trend in prescriptions would have continued in the absence of this policy change, there were 34,000 fewer prescriptions per quarter in this population by the end of the second quarter of 2005. If we extrapolate from the GPRD population to the UK population of approximately 60 million, we predict approximately 350,000 fewer statin prescriptions per quarter in the UK due to this policy change. Conclusion: Our study suggests that the policy allowing the OTC sale of 10 mg simvastatin has had an immediate and substantial impact on statin prescriptions. However, this new policy may also be leading to an era of less aggressive statin therapy. 8:15 a.m. 808-8 The Triglyceride/High Density Lipoprotein Ratio Predicts All-Cause Mortality in Women Vera Bittner, B. Delia Johnson, Issam Zineh, Genevieve Barrow, William Rogers, C. Noel Bairey-Merz, George Sopko, University of Alabama at Birmingham, Birmingham, AL, University of Pittsburgh, Pittsburgh, PA Background: Triglycerides (TG) and HDL cholesterol are important cardiovascular (CV) risk factors in women. The TG/HDL ratio is a marker for insulin resistance and small dense LDL particles. Information about its prognostic utility in high risk women is limited. Methods: We studied 537 women without history of CVD enrolled in the Women’s Ischemia Syndrome Evaluation (WISE). All were referred for coronary angiography for suspected myocardial ischemia. Fasting lipid proﬁles and detailed demographic and clinical data were obtained at study entry. Median follow-up was 5.8 years. Multi-variate Cox-proportional hazards models for all cause mortality and CV events (death, MI, CHF, stroke) were constructed using log TG/HDL ratio as a predictor variable and taking important CVD risk factors into account. Results: Mean age was 57+/-11 years, 84% were white, 54% hypertensive, 20% diabetic, 51% had a history of smoking. Deaths (n=34) and CV events (n=80) increased across TG/ HDL quartiles (graph; both p<0.01 for trend). TG/HDL was a strong independent predictor of all cause mortality in models adjusted for age, race, smoking, hypertension, and diabetes (HR 2.11, 95% CI 1.13, 3.94, p=0.02). For CV events, the multivariate HR was 1.45 (95% CI 0.98,2.14, p=0.06). Adjustment for lipid-lowering therapy did not affect the results. Conclusions: Among women evaluated for suspected ischemia, the TG/HDL ratio is a powerful independent predictor of all cause mortality. POSTER SESSION 956 Stenting, Restenosis, and Smooth Muscle Cells Monday, March 13, 2006, 9:00 a.m.-12:30 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 956-159 Different Genetic Make-up of the Anti-inﬂammatory Il10- gene Contributes to the Development of Restenosis After PCI D. Pons, P. S. Monraats, F. R. de Vries, A. H. Zwinderman, M. P.M. de Maat, P. E. Slagboom, W. R.P. Agema, P. A.F.M. Doevendans, R. J. de Winter, R. A. Tio, J. Waltenberger, R. R. Frants, A. van der Laarse, E. E. van der Wall, J. W. Jukema, Leiden University Medical Center, Leiden, The Netherlands Background: Genetic factors appear to be important in the development of restenosis after percutaneous coronary intervention (PCI), as well as in the process of inﬂammation, a pivotal factor in restenosis. IL-10 predominantly exerts anti-inﬂammatory activities. Therefore the aim of this study was to examine whether different polymorphisms in the genetic code of this gene are related to the risk of development of restenosis, deﬁned by TVR after PCI. Methods: The GENetic Determinants of Restenosis (GENDER) project is a multicenter prospective follow-up study, including patients treated with successful PCI. Genotyping was performed by MassArray platform (Sequenom). Results: A total of 3,104 patients, age 62.1±10.7 years, had a follow-up with a median duration of 9.6 months (interquartile range 3.9). Genotyping was performed for the following polymorphisms in the IL10 gene: -592G/T, -2849G/A, -1082G/A and 4251C/T. Allele frequencies were; 0.76/0.24, 0.72/0.28, 0.51/0.49 and 0.73/0.27, respectively. After adjusting for clinical variables three out of the four IL-10 polymorphisms were signiﬁcantly associated with TVR (-2849G/A: RR; 1.7, 95%CI; 1.2-2.5, -1082G/A: RR; 1.4, 95%CI; 1.1-1.8, and 4251C/T: RR; 2.0, 95%CI; 1.4-2.8). The -592G/T polymorphism did not show a signiﬁcant association. Conclusions: The present study shows that three polymorphisms of the IL10 gene are associated with the development of restenosis after PCI. IL-10 is associated with inhibition of IL-1β release by circulating leukocytes and reduced inﬁltration of the arterial wall by activated macrophages. After conﬁrmation by another large study, screening patients for this genotype can lead to a better risk stratiﬁcation and to a more tailored therapy for patients to prevent restenosis after PCI. 956-160 Late Angiographic Stent Thrombosis (LAST) After Bare- Metal Stent Versus Drug-Eluting Stent Implantation Duk-Woo Park, Seong-Wook Park, Young-Hoon Jeong, Eui-Seock Hwang, Se-Whan Lee, Young-Hak Kim, Bong-Ki Lee, Cheol Whan Lee, Myeong-Ki Hong, Jae-Joong Kim, Seung-Jung Park, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea BACKGROUND: Last angiographic stent thrombosis (LAST) events have recently been issued after drug-eluting stent (DES) implantation, which had been regarded as very uncommon phenomenon with bare-metal stent (BMS) except after coronary brachytherapy. METHODS: We investigated the incidence and clinical characteristic of LAST events in consecutive 3,940 patients with BMS vs. 1,905 patients with DES. LAST was deﬁned as angiographically conﬁrmed stent thrombosis with acute ischemic symptoms at least 1 month after stent implantation. RESULTS: There were seven cases (0.18%, 95% CI 0.05% to 0.31%) of LAST in patients with BMS (median 5.3 months, range of 2.3 months to 73.2 months) and 5 cases (0.26%, 95% CI 0.03% to 0.49%) in patients with DES (median 5.2 month, range of 1.6 months to 20.4 months) (p=0.55). Baseline clinical and procedural characteristics were similar between two groups. Initial thrombus-containing lesions for intervention were found in 2 cases (29%) with BMS vs. no case with DES (p=0.43). Complete discontinuation of antiplatelet therapy was found in 2 cases (29%) with BMS vs. 3 cases (60%) with DES (p=0.56). Two cases (29%) with BMS and 2 cases (40%) with DES developed LAST while patients were on dual antiplatelet therapy (aspirin plus cilostazol in BMS and aspirin plus clopidogrel in DES). There was no death associated with LAST in two groups. CONCLUSIONS: In this large, unselected population, the incidence of LAST was similar between the BMS group and the DES group. Further studies would be necessary to identify the patients with high risk of LAST and to determine optimal antiplatelet regimen for these patients. 956-161 Rotational Atherectomy With Sirolimus Eluting Stents Versus Rotational Atherectomy With Bare Metal Stents for Complex Coronary Calciﬁc Lesions Gaurav Minocha, Sanjay Chugh, Vivek Tandon, Mitu Anand Minocha, Praveer Agarwal, Madhukar Shahi, Balbir Singh, Atul Mathur, Ashok Seth, Suman Bhandari, Tarlochan Singh Kler, Escorts Heart Institute and Research Centre, New Delhi, India Background: Large Percutaneous Coronary Intervention (PCI) trials on Drug Eluting Stents have excluded vessels with signiﬁcant calciﬁcation and those requiring rotablation. There is lack of data data on rotablation with Sirolimus Eluting Stents (SES) in severely calciﬁc lesions. Methods: We compared the early and mid term clinical outcomes between rotational atherectomy with SES (110 patients) and rotational atherectomy with Bare Metal Stents (106 patients). ACC_2006_8_VascularDisease.indd 317 1/4/06 5:21:05 PM 318A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n Results: Baseline characteristics were similar between the two groups. Diabetics constituted 45% in SES group and 40.5% in BMS group (p=NS). Mean LV ejection fraction (LVEF) was 49.7 ± 10.5% in SES group and 45.2 ± 9.8% in BMS group (p = NS). Mean vessel size was 2.86 ± 0.2 mm in SES group and 3.0 ± 0.2 mm in BMS group (p = NS). Procedural success was similar between the 2 groups. There was no signiﬁcant difference in the in hospital complications between the 2 groups. Clinical follow up was available in 97.2% patients in the SES versus 94.3% patients in the BMS group. During a mean follow up 18.2 ± 6.4 months in the SES group, 4 patients died compared to 5 deaths in the BMS group. The target lesion revascularisation was lower in the SES group versus BMS group (4.6% vs 15%, p = 0.014). The total Major Adverse Cardiac Event rate was also better in the SES group versus the BMS group (9.7% vs 23%,p = 0.02). Conclusions: Rotational atherectomy followed by Sirolimus Eluting Stents in complex calciﬁc coronary lesions is associated with a good mid term outcome. Compared with Bare Metal Stents, Sirolimus Eluting Stents are associated with better results because of lesser target vessel revascularisations in calciﬁc lesions treated initially with rotational atherectomy. 956-162 Evaluation of Neointimal Hyperplasia by Optical Coherence Tomography at Six-Month After Sirolimus- Eluting Stent Deployment Daisuke Matsumoto, Junya Shite, Toshiro Shinke, Satoshi Watanabe, Hiromasa Otake, Yusuke Imuro, Daisuke Ogasawara, Takahiro Sawada, Oscar Luis Paredes, Mitsuhiro Yokoyama, Kobe University Graduate School of Medicine, Kobe, Japan BACKGROUND Whether Sirolimus-eluting stent (SES) has neointimal coverage at chronic phase remains to be clariﬁed. Optical coherence tomography (OCT) with excellent resolution may visualize thin intima on SES strut which intravascular ultrasound (IVUS) could not detect. METHODS We evaluated 47 SES (28 patients) by OCT and IVUS with every 1 mm cross section at 6 months after SES deployment. Strut apposition to the vessel wall and thickness of intima on each strut surface was evaluated. These struts were categorized into well-apposed with intima (WI+), well-apposed without intima(WI-) and mal-apposition (Mal). RESULTS OCT could quantify intimal thickness on each strut surface (average 97.2µm) and the number of struts covered with intima<100µm (beyond IVUS resolution) was 3,233 out of whole 5,366 struts. By OCT, 4,881 (91%) struts were WI+, 367 (6.8%) were WI- and 118 (2.2%) were Mal. Although there was no difference in proportion of WI+, WI- and Mal between stent edge and body, Mal was more frequent in overlapped stent area (30/342 struts, 8.8%) than in non-overlapped (88/5024, 1.8%) and also Mal was more prevalent in previous total occluded area before intervention (70/1343, 5.2%) than in non-occluded area (48/4023, 1.2%). Suspect of thrombus attached to struts were observed at 1 Mal stent. CONCLUSION:Most of SES struts were covered with neointima at 6 months after deployment when observed with OCT. Overlapped stent area and previous total occluded area may predispose to mal-apposition leading to thrombosis. 956-163 Percent Plaque Area at the Edge of Sirolimus-Eluting Stent Predicts Restenosis in Small Vessel Coronary Arteries Yuichi Uchino, Sakakibara Heart Institute, Fuchu City, Tokyo, Japan Background: Predictors of restenosis in small vessels implanted with sirolimus-eluting stent (SES) remain unknown. We evaluated whether percent plaque area (%PA) at the stent edge measured by intravascular ultrasound (IVUS) after the procedure is associated with mid-term restenosis. Methods: We analyzed 31 patients, 36 lesions (72 edges) with ≤2.5mm reference diameter (mean 2.26±0.20mm) implanted with SES from August 2004 to September 2005 in our hospital. %PA within 5mm to the proximal and distal edge of the stent after the procedure was measured by IVUS and angiographic follow-up was performed 8 months after the implantation. Results: Restenosis (%diameter stenosis > 50) was found in 7 lesions (19.4%) and target lesion revascularization was performed in 3 cases. All restenosis occurred at the proximal (n=5) or distal (n=2) stent edges. No in-stent restenosis was observed. None of diabetes mellitus, hypertension, hyperlipidemia, minimum stent area after the procedure, reference diameter, nor lesion length showed signiﬁcant correlation with restenosis. %PA after the procedure was; 46.0±13.3% (n=7) in restenotic edges, 28.4±12.6% (n=65) in non-restenotic edges (p=0.0058). Restenosis rate was 45.5% vs. 3.3% in the group of ≥45% vs. <45% of %PA (p<0.01). Conclusions: %PA at the edge of the stent on IVUS is a predictor of mid-term restenosis in small vessels implanted with SES. 956-164 Predictors of Stent Thrombosis After Drug-Eluting Stents Implantation During Long-Term Follow-Up Seong-Wook Park, Duk-Woo Park, Young-Hoon Jeong, Eui-Seock Hwang, Se-Whan Lee, Bong-Ki Lee, Young-Hak Kim, Cheol Whan Lee, Myeong-Ki Hong, Jae-Joong Kim, Seung-Jung Park, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea BACKGROUND: Data are limited regarding the true rates of stent thrombosis (ST) after drug-eluting stent (DES) implantation in real-world practice. METHODS: We investigated the frequency and risk factors of ST after DES implantation in 1,911 patients (2,608 lesions; sirolimus-eluting stent in 1,545 patients, 2,045 lesions and paclitaxel-eluting stent in 366 patients, 563 lesions) during long-term follow-up. RESULTS: During long-term follow up (median 17.4 month), 15 patients (0.8%, 95% CI 0.4% to 1.2%) developed ST (median 4.4 month, range 0.1-20.4 month). Four patients (0.2%) had subacute ST and 11 patients (0.6%) had late thrombosis. The incidence of ST did not differ according to stent types (0.7% in sirolimus-eluting stents vs. 1.1% in paclitaxel-eluting stents, p=0.7). Independent predictors of ST were primary stenting in acute myocardial infarction (HR 32.3, 95% CI 6.8-154.3, p<0.001), renal failure (HR 7.4, 95% CI 1.6-34.1, p=0.010) and total stent length (HR 1.03, 95% CI, 1.01-1.05, p=0.007 for each 1 mm increase). Discontinuation of antiplatelet therapy was found in 7 patients (64%) with late ST, but not in patients with subacute ST. CONCLUSIONS: In a single center, large cohort of patients undergoing DES, the incidence of ST during long-term follow-up was a 0.8%. Primary stenting in AMI, renal failure and total stent length were identiﬁed as predictors of ST. Discontinuation of antiplatelet therapy was strongly associated with the development of ST in more than half of patients with late ST. 956-165 Polymer Based Paclitaxel-eluting Stents Are Superior to Non-polymer Based Paclitaxel-eluting Stents in the Treatment of De-novo Coronary Lesions: An Intravascular Ultrasound Study Ekaterina Ioﬁna, Jörg Schröder, Roswitha Langenberg, Andreas Franke, Harald Kuehl, Karl Christian Koch, Peter Hanrath, Rainer Hoffmann, University, Aachen, Germany Background: Whether polymer based paclitaxel eluting stents are superior to non- polymer based paclitaxel eluting stents has not been evaluated. This study compared the clinical, angiographic and intravascular ultrasound (IVUS) outcomes of patients treated with polymer vs. non-polymer based paclitaxel-eluting stents. Methods: 60 consecutive patients (63 de-novo lesions) treated with polymer based paclitaxel-eluting stents (TAXUS®, 1 µg/mm2 paclitaxel, Boston Scientiﬁc Corp.) and 60 consecutive patients (62 de-novo lesions) treated with non-polymer based paclitaxel- eluting stents (V-Flex Plus®, 2.7µg/mm2 paclitaxel, Cook Inc) were enrolled in the study. 6-month angiographic follow-up was performed on 54 lesions of the TAXUS group and 50 lesions of the V-Flex Plus group. In the ﬁrst 30 patients of both stent groups IVUS follow- up was intended. Intimal hyperplasia area and thickness were calculated as mean over the total stent length. Results: Baseline clinical, angiographic and IVUS characteristics were comparable between both groups with lesion length of 10.3±4.1 and 11.2±3.9 mm (P=0.45) and reference vessel diameter of 2.91±0.49 and 2.98±0.44 mm (P=0.55) in the TAXUS- and V-Flex stent group, respectively. Polymer based Paclitaxel elution Non-polymer based Paclitaxel elution P Late loss (mm) 0.24±0.28 0.59±0.51 0.001 Restenosis rate (%) 9 24 0.082 Mean IH area (mm2) 0.62±0.41 2.24±1.46 <0.001 Mean IH thickness (mm) 0.06±0.04 0.23±0.19 <0.001 Target lesion revascularization (%) 8 20 0.122 ACC_2006_8_VascularDisease.indd 318 1/4/06 5:21:06 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 319A Vascular D isease, H ypertension, and P revention Conclusions: Implantation of polymer based paclitaxel-eluting stents results in superior angiographic and IVUS follow-up outcomes compared to non-polymer based paclitaxel- eluting stents. 956-166 A New Concept of Local Paclitaxel Delivery for Prevention of Restenosis: Intracoronary Paclitaxel Delivery With the New Genie®-application Device Christian Herdeg, Christoph Dommke, Stephen Schroeder, Tim Sueselbeck, Meinrad Gawaz, Gisela Toncar-Pﬂumm, Kathrin Göhring, Karl K. Haase, Tuebingen University Medical School, Tuebingen, Germany, Mannheim University Medical School, Mannheim, Germany Background: With the rapid expansion of drug eluting stents (DES) it becomes obvious, that not all problems will be solved with this technology. In particular the stent coating material causes concern, since it has potential thrombogenic and inﬂammatory effects, and also the fate of the coating itself, after the drug has been released, remains unclear. Paclitaxel is a promising candidate for a local intracoronary delivery independent of the stent itself by using catheter techniques because of its long-lasting effects even after single-dose administration. Besides the fact, that no problematic coating as drug carrier has to be used, this technique offers further advantages - such as the possibility to treat the whole vessel wall and not only the area around the stent struts. Even more importantly, the stent edges and adjacent vessel segments can be covered by pharmacotherapy to avoid the so called “edge-effect” of drug eluting stents. Methods: We have developed a new local delivery system together with ACROSTAK Corp, the so-called GENIE®-catheter for local paclitaxel delivery. Basically this system consists of a percutaneous balloon having a distal and proximal segment with occlusive function and a central segment that allows for homogenous transfer of paclitaxel to the stented vessel wall. Three holes in the distal ramp ﬁll the drug depot without additional trauma or hydrojets. Results and conclusion: A recent animal study using local paclitaxel delivery with the GENIE®-catheter in 30 domestic pigs showed excellent results. After 6 weeks observation period neointimal area was reduced from 60.4±5.5% in the control group (overstretch injury, bare metal stent) and 53.8±20.9% in sham operated animals to 17.0±2.1% in paclitaxel-treated animals (p≤0.001). This development has led to a large clinical prospective, randomized multicenter trial in 204 patients in Germany. The LOCAL- TAX study compares the “local intracoronary delivery of paclitaxel after stent implantation for prevention of restenosis in comparison with implantation of a bare metal stent alone or with implantation of a paclitaxel-coated stent”. Patient enrolment started in summer 2005, 30 days MACE will be available in spring 2006. 956-167 Paclitaxel-Eluting Stents Implanted in De- Endothelialized Coronary Arteries for 180 Days Did Not Cause Luminal Thrombi Using Standard Antiplatelet Therapy Arturo Garcia-Touchard, John E. Heil, Igor Polyakov, Sylvester Price, Bradley C. Poff, Mary E. Russell, Robert S. Schwartz, Minneapolis Heart Institute Foundation, Minneapolis, MN, Boston Sci, Minneapolis, MN Introduction Drug-eluting stents are associated with delayed arterial healing and endothelialization post implantation in both animals and human studies. We have developed a thermal injury-induced drug-eluting stents efﬁcacy model in pigs, characterized by an extensive endothelial cell death, delay healing and extraordinary neointimal proliferation. This lesion provides an opportunity to assess the thrombotic risks of drug eluting stents in an adverse environment. Methods Sixty-six bare Express2 (BMS) and 63 paclitaxel (PTx-) Express2 (1 µg/mm2, slow-release formulation) stents were placed in 45 domestic pigs immediately after coronary thermal balloon injury (78-83oC, 2 x 15 sec) using a stent-artery ratio of 1.1:1. All animals received aspirin (325mg PO qd.) and clopidogrel (75 mg/day) 3 days prior to implantation until termination. Stents were explanted after 7, 28, 90 and 180 days and histopathology was evaluated. Results uminal endothelialization did not differ between BMS and PTx stent at follow up endpoints. At 180 days <75% of the lumen circumference was covered by endothelial cells in both groups. There were subluminal inﬂammation, moderate para-strut ﬁbrin and medial necrosis in both but delayed in PTx group (peak at 28 days in BMS and 90 days in PTx). Despite thermally-induced delayed healing, stent thrombosis-induced occlusion was not observed. Only microthrombi at 7 days follow up were present in 5 of 14 PTx stents and in 1 of 13 bare metal stents (p > 0.05). Conclusion With conventional antiplatelet therapy, stent thrombosis and/or luminal thrombi were not attributable to PTx stents in this thermal injury porcine model. PTx stent morphology was comparable to bare metal stent. The lack of thrombi was noteworthy given delayed endothelialization and thermally-induced subluminal inﬂammation, moderate para-strut ﬁbrin and medial necrosis (all increase the risk of instent thrombosis) and indicate efectiveness of double antiplatelet therapy.These ﬁndings are concordant to clinical studies and support the continuation of antiplatelet regimen in human cases where a propensity for stent thrombosis is suspected. 956-168 Link of Serum CK Activities to Vascular Smooth Muscle Revealed by Physiological-genomic Analyses of Statin- treated Patients Gualberto Ruano, Paul D. Thompson, Richard L. Seip, Andreas Windemuth, Wu Alan, Andrew Smith, Theodore R. Holford, Mohan Kocherla, Genomas, Hartford, CT, Hartford Hospital, Hartford, CT Background: Side effects ranging from mild myalgia (weakness, fatigue, pain, cramps) to frank rhabdomyolysis are reported by 3-25% of patients taking statins to lower blood cholesterol. Physiological origins may be neural, muscular, and/or vascular. Elevated serum creatine kinase (CK) activity often accompanies the symptoms. We employed concerted physiological-genomic analyses to investigate the relationship between CK activity and selected gene variants. Methods: We screened for genetic associations with serum CK levels in 102 patients receiving atorvastatin or simvastatin therapy for hypercholesteremia. A total of 19 single nucleotide polymorphisms (SNPs) were selected from 10 candidate genes involved in vascular homeostasis. Multiple linear regression analysis was used to rank the SNPs according to probability of association. The false discovery rate (FDR) procedure was applied to account for multiple testing. Results: SNPs in the angiotensin II Type 1 receptor (AGTR1, p=0.002, FDR=0.041) and nitric oxide synthase 3 (NOS3, p=0.005, FDR=0.047) genes were signiﬁcantly associated with CK activity. Less pronounced were relationships between angiopoietin1 (ANGPT1, p=0.016, FDR=0.1), oxytocin (OXT, p=0.022, FDR=0.11), FMT-related tyrosine kinase 1 (FLT1, p=0.037, FDR=0.14) and CK. No relationships were found between CK and EDN1 (endothelin 1), SELP (selectin P), SELE (selectin E), OLR1 (oxidized low-density lipoprotein receptor), and SERPINE1 (serpin peptidase inhibitor clade-E). Conclusions: These results demonstrate a strong association between CK activity during statin treatment and variability in genes related to vascular function. We propose the testable hypothesis that alteration in vascular smooth muscle function contributes to statin-induced muscle injury. 956-169 Amlodipine Modulates the MEK1 and ERK Pathway to Induce Vascular Smooth Muscle Cell Differentiation In Vivo Seiji Umemoto, Shinji Kawahara, Kyoko Umeji, Ryo Hashimoto, Masunori Matsuzaki, Pharmaceutical Clinical Research Center, Yamaguchi University Hospital, Ube, Japan, Yamaguchi University Graduate School of Medicine, Ube, Japan Background: The calcium antagonists have been widely used in the treatment of patients with hypertension, in whom they inhibit cardiovascular events as effectively as angiotensin-converting enzyme inhibitors. In addition, recent clinical studies have revealed that the long-acting L-type dihydropyridine calcium antagonist amlodipine may have antiatherogenic properties independent of its effects on vasodilatation. The molecular mechanisms of the antiatherogenic property of amlodipine, however, remain unknown. This study was designed to examine which signal transduction pathway might be important for the antiatherogenic property of amlodipine, as assessed by aortic smooth muscle cell (SMC) phenotypes in hypertension in vivo. Methods and Results: Stroke-prone spontaneously hypertensive rats (SHRSPs) were randomly treated with a vehicle, amlodipine, or enalapril while Wister-Kyoto rats (WKY) used as controls were treated with only the vehicle. Both drugs were equally effective at reducing systolic blood pressure and aortic morphology in comparison to vehicle-treated SHRSP aortas. In the vehicle SHRSP aortas, contractile-type SM myosin heavy chain (MHC) SM2 was signiﬁcantly lower, whereas synthetic-type MHC NMHC-B/SMemb was signiﬁcantly higher compared with those in the vehicle WKY aorta. Compared to the vehicle SHRSP group, both drugs signiﬁcantly and equally induced aortic SMC phenotype in SHRSP toward the differentiated state by reducing NMHC-B/SMemb and increasing SM2. In the vehicle SHRSP group, MKK6, p38 MAPK, MEK1 and p-42/44 ERK were signiﬁcantly increased compared with the WKY group. Both drugs signiﬁcantly reduced these values in the SHRSP aorta. Furthermore, amlodipine but not enalapril signiﬁcantly lowered MEK1 and p-42/44 ERK to the same levels as in the WKY group, whereas enalapril was more effective than amlodipine at increasing p-Akt and eNOS in SHRSP aortas, which were signiﬁcantly lower in the vehicle SHRSP group than in the WKY group. Conclusions: The MEK/ERK pathways might be crucial determinants of aortic SMC phenotype activated by amlodipine treatment of hypertension in vivo. 956-170 Vascular Smooth Muscle Cells From Stable and Unstable Atherosclerotic Plaques Show Epigenetic Commitment Even After 25 Plating Passages Marco L. Rossi, Pierangelica Merlini, Nicola Marziliano, Enzo Bramucci, Diego Ardissino, Ospedale Maggiore di Parma, Parma, Italy Background. Unstable angina and myocardial infarction are the clinical manifestations of the abrupt thrombotic occlusion of an epicardial coronary artery as a result of spontaneous atherosclerotic plaque rupture or ﬁssuring, and the exposure of highly thrombotic material. Proliferation of vascular smooth muscle cell (VSMC) and differential expression of inﬂammatory and apoptotic markers have been demonstrated to be among one of the most important mechanisms in the atherosclerosis progression. The combined over-expression of inﬂammatory and pro-apoptotic genes from the VSMC may be the initial triggering for both plaque rupture and thrombotic response. Our aim was to collect those VSMC from atherosclerotic plaques and establish stabile, long term primary cell cultures as model for biochemical and molecular genetics studies. Methods and Results. We have isolated VSMC from 15 patients with stable angina (SA) and 15 with acute coronary syndromes without ST elevation (ACS) after dissection under light microscopy. VSMC grown out from the explants after 10-15 days in Hams F12 supplemented with 10 % FCS, were conﬁrmed to be smooth muscle cells by their typical hill and valley morphology and by alpha-actin immunoﬂuorescent staining up to 25 plating passages before undergoing cellular senescence. We also proﬁled gene expression at each plating passage via microarray analysis. We also applied small interfering RNA (siRNA) to revert the ACS pattern into SA and viceversa. The different gene expression proﬁling for all the biological functions in VSMC cultured cells from ACS and SA plaques was kept in in vitro conditions up to 25 passages. The phenotypic reversibility of ACS and SA VSMC was possible up the 15 passage, while only SA to ACS transitions were allowed after this time-point. We have demonstrated through molecular and cellular studies that the cell differentiation between SA and ACS VSMC is kept in primary cell cultures up to 25 plating passages thus letting to speculate that epigenetic mechanisms might underlie this differentiation. Furthermore, we propose a new cell system model for studies on the pathophysiology of unstable angina and myocardial infarction ACC_2006_8_VascularDisease.indd 319 1/4/06 5:21:06 PM 320A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n 956-171 Blockade of RAGE With a New Fusion Protein Suppresses Neointimal Formation in Both Diabetic and Non-Diabetic Rats After Vascular Injury Zhongmin Zhou, Yanming Huang, Eric J. Topol, Adnan M.M. Mjalli, Jeffery C. Webster, Ye E. Tian, Jane M. Shen, Kai Wang, Marc S. Penn, Robert Rothlein, The Clevealnd Clinic Foundation, Cleveland, OH Background: The receptor for advanced glycation endproducts (RAGE) and its ligands have been shown to play a key role in arterial injury, especially in diabetes. We evaluated the effects of a fusion protein (TTP4000) on SMC proliferation and neointimal formation in both diabetic and nondiabetic rats. Methods: Balloon injury of left common carotid artery was performed in Zucker diabetic and nondiabetic rats using a standard procedure. A loading dose (3 mg/rat) of IgG, TTP4000, or PBS was administered intraperitoneally one day prior to injury, A maintenance dose (high dose group, 1mg/rat; low dose group, 0.3/rat) was delivered every other day until day 7 after injury. Animals were sacriﬁced at 4 days and 21 days. For the day 4 animals, rat received intraperitoneal injection of bromodeoxyuridine (BrdU) 50 mg/kg at 18, 12, and 2 hours before euthanasia. VSMC proliferation was assessed. Van Gieson staining and morphometric analyses were performed on day 21 animals. All data were expressed as mean ± SD. A value of P<0.05 was considered to be statistically signiﬁcant. Results: The number of BrdU-labeled proliferating cells was signiﬁcantly reduced in the high dose TTP4000 treated group compared with controls in diabetic rats (29.67±4.80 versus 68.17±34.01; P<0.05). Similar reduction was also observed in nondiabetic rats (28.43±10.44 versus 48.86 ±17.08; P<0.05). There was a dose dependent decrease in neointimal area in both diabetic and nondiabetic rats. In diabetic rats, there was a 20% reduction in neointimal area in high dose TTP4000 treated compared with that observed in IgG treated animals (0.16±0.03 versus 0.20±0.03 mm2, P<0.01), and a reduction in I/M ratio was also observed (1.42±0.16 versus 1.71±0.27; P=0.02). In nondiabetic rats, there was a 30% decrease in neointimal area (0.09±0.05 versus 0.14±0.03 mm2; P = 0.04), and a reduction in I/M ratio (0.89±0.41 versus 1.27±0.29; P< 0.05) in the high dose TTP4000 treated rats compared with that in control. Conclusion: Blockade of RAGE/ligands interaction with TTP4000 suppresses VSMC proliferation and minimizes neointimal formation in a dose-dependent manner in both diabetic and non diabetic rats subjected to vascular injury. 956-172 Micro-Computed Tomographic Scanning of Stented Coronary Arteries Is Feasible, and Image Analysis Reliably Quantiﬁes the Coronary Vasa Vasorum Density Seyed M. Hashemi, Robert L. Wilensky, Charles Q. Li, Kambiz Parcham-Azad, Jeffrey A. Kohn, Robert S. Schwartz, Hidehiko Hara, Robert A. Herrmann, Jody Crary, Alexander C. Wright, University of Pennsylvania, Philadelphia, PA, Minneapolis Heart Institute, Minneapolis, MN Background: The association of vasa vasorum neovascularization with atherosclerosis and restenosis has received considerable recent attention. Micro-CT scanning of coronary arteries can visualize and quantify their vasa vasora. However, this novel imaging technology has not been applied to stented coronary arteries, possibly due to artifacts created by metal stents. The objective of this study was to develop a methodology to generate, process and analyze 3-dimensional (3-D) micro-CT images of stented coronary arteries in order to reliably quantify the density of their vasa vasora. Methods: Yorkshire swine (25-40 kg, n=14) underwent metallic stent implantation in coronary arteries (LAD and LCX, total of 28 stents). At 28 days the animals were euthanized, and coronary arteries perfused with radiopaque Microﬁl®(Flow Tech). The stented vessels were harvested next day and scanned. From the reconstructed 3-D micro-CT data set, a 50-slice slab (1.2 mm thick) was analyzed at ﬁve locations along the artery, 3 within the stent area and 2 outside. By blanking from the analysis the stent, veins, coronary branches, and air, a true vasa volume fraction (VF) in each slab was calculated. Also, using a bone stereology analysis tool, average vasa diameter (D) was calculated. Results: Vasa vasora in micro-CT images appeared evenly distributed in all tissue blocks, reﬂecting proper Microﬁl perfusion technique. While the stent struts created severe local artifacts, these could be effectively blanked from the analysis. The endpoints for all 28 samples obtained from slabs located in the stent (N=84) versus slabs located in the tissue outside the stented area (N=56) resulted in the following values respectively (mean ± SD): VF = 4.9% ± 0.3% vs. 3.9% ± 0.2% (p value=0.04), D=96±18µ vs. D=104±25µ (p value=0.02). These data demonstrate signiﬁcantly increased vasa volume fraction and reduced mean vasa diameter in the stented areas as compared to non-stented areas of arterial wall. Conclusion: 1. Micro-CT scanning of stented coronary arteries is a feasible and reliable method to quantify the density of their vasa vasora. 2. Stent implantation promotes neovascularization in coronary artery vasa vasora. POSTER SESSION 957 Effects on Therapy and Atherosclerosis Monday, March 13, 2006, 9:00 a.m.-12:30 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 957-173 Statin Cools Down Temperature of Atherosclerotic Plaque in Patient With Coronary Artery Disease: Temperature Measurement and Intravasular Ultrasound Study So-Yeon Choi, Byoung-Joo Choi, Seung-Jea Tahk, Myeong-Ho Yoon, Sung-Gyun Ahn, Zhen-Guo Zheng, Hong-Seok Lim, Jung-Hyun Choi, Soo-Jin Kang, Gyo-Seung Hwang, Joon-Han Shin, Ajou University School of Medicine, Suwon, South Korea Background: Because an increase of temperature is associated with expression of aggressive inﬂammation in plaque, the measurement of plaque temperature can be used to assess plaque vulnerability. This study was planed to investigate the effect of statin on stability of plaque by assessing temperature using RADI PressureWireTM and RADIanalyserTM (RADI Medical System AB, Sweden) that reveals the temperature difference (ΔT, °C) between atherosclerotic plaque and normal healthy vessel wall. Methods: We included angina patients who were planed to take coronary intervention, had signiﬁcant stenosis on diagnostic coronary angiogram performed by radial artery approach in out-patient clinic and then evenly randomized into two groups: statin (pravastatin 40mg/ d) or control group. The temperature measurement and IVUS study were performed at baseline (during diagnostic angiogram) and at 4-week follow-up (just before intervention). All patients had taken same medications except statin during study period. Results: 28 angina patients (age range, 48-72; 64% men; 64% unstable angina) were enrolled (14 in statin group, 14 in control group). The average time interval between baseline and follow-up was 29±6 days. On IVUS study, there were no signiﬁcant differences of quantitative and qualitative parameters between baseline and follow-up in both groups. The baseline ΔT were not signiﬁcantly different between two groups (statin; 0.25±0.14 vs. control; 0.23±0.11, p=0.674) but statin group had a signicant decrease of �T during follow-up period (p=0.002) and a lower follow-up ΔT (statin; 0.13±0.07 vs. control; 0.21±0.14°C, p=0.036). And the reduction of ΔT (follow-up ΔT - baseline ΔT) was signiﬁcantly greater in statin group compared to the control group (statin; -0.12±0.09 vs. control; -0.01±0.07 , p=0.010). Conculsions: Even though a major limitation of this study is the very small number of enrolled patients, this study provides evidence in support of the anti-inﬂammatory effect of statins in human coronary plaque and also reveals that physiologic change like a decrease of temperature procedes any morphologic change in processing reduction of plaque vulnerability. 957-174 Determinants of Arterial Wall Remodeling During Lipid Lowering Therapy. Serial IVUS Observations from the REVERSAL Trial. Paul Schoenhagen, E. Murat Tuzcu, Carolyn Apperson-Hansen, Ilke Sipahi, Stephen Nicholls, William A. Magyar, Aaron Loyd, Tammy Churchill, Tim Crowe, Steven E. Nissen, The Cleveland Clinic Foundation, Cleveland, OH Background:Coronary plaque progression and lesion instability are associated with expansive remodeling of the vessel size. However, the arterial wall remodeling response during plaque stabilizing therapy and the relationship to serum markers of lipid metabolism and inﬂammation is incompletely understood. Methods:We analyzed serial intravascular ultrasound (IVUS) data from the REVERSAL trial obtained during 18 months of intensive versus moderate lipid-lowering treatment. In a subgroup of 210 patients, focal coronary lesions with mild luminal stenosis and adjacent proximal reference sites were identiﬁed. Lumen area, external elastic membrane (EEM) area, and plaque area were determined at the lesion and reference sites at baseline and follow-up. The remodeling ratio (RR) was calculated by dividing lesion EEM area by reference EEM area. The percent change of the remodeling ratio between baseline and follow-up was calculated. The relationship between change in remodeling, changes in plaque burden, lipid proﬁle and inﬂammatory markers was examined in multivariable analysis. Results:The baseline plaque burden at lesion and reference sites were 49.9±9.9% and 29.5±7.8%. At the lesion site, progression in plaque area [+8.9±25.7%] and a decrease in the remodeling ratio [-3.0±11.2%] occurred during follow-up. In multivariate analysis, variables independently correlated with the percent change of remodeling ratio were: percent change in plaque area (p < 0.0001), log-change in CRP (p = 0.03), percent change in triglyceride levels (p = 0.02), lesion location in RCA (p = 0.01), and presence of hypertension at baseline (p = 0.01). In contrast, change in LDL, HDL, and treatment group did not show an independent relationship to remodeling. Conclusions: These results demonstrate that direction of arterial remodeling correlates with changes in plaque burden. Plaque stabilizing therapy is associated with contrictive remodeling. The independent relationship to CRP suggests an important inﬂuence of inﬂammation in the pathophysiology of remodeling. 957-175 Use of Beta-Blockers and Progression of Coronary Atherosclerosis: An Intravascular Ultrasound Analysis from the CAMELOT Study Ilke Sipahi, E. Murat Tuzcu, Stephen J. Nicholls, Paul Schoenhagen, Okan Gulel, Aaron B. Loyd, Tammy Churchill, Samir Kapadia, Steven E. Nissen, Cleveland Clinic Foundation, Cleveland, OH Background: Beta-blockers have been shown to decrease mortality in patients with myocardial infarction. However, the effect of beta-blockers on progression of coronary ACC_2006_8_VascularDisease.indd 320 1/4/06 5:21:07 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 321A Vascular D isease, H ypertension, and P revention atherosclerosis is largely unknown. Our aim was evaluate this by using serial intravascular ultrasound (IVUS). Methods: Patients enrolled in the IVUS substudy of the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study were included. Patients underwent IVUS of a single coronary artery at baseline, which was repeated after 2-years of treatment with amlodipine, enalapril, or placebo. For the purpose of this substudy, the outcome measure of change in total atheroma volume (TAV) was compared in patients who were on concomitant beta-blocker treatment during the trial (n=225) and those who were not (n=49). Results: Patients on beta-blockers were more likely to be hypertensive (Table). Without any adjustment for possible confounders, change in TAV was not signiﬁcantly different in the two groups (p=0.28). After adjusting for hypertensive status, study treatment, systolic blood pressure, and lipid levels, patients undergoing beta-blocker treatment had a signiﬁcantly lower change in TAV as compared to those who were not (p=0.03). Conclusion: The results of this observational analysis suggest that beta-blockers slow progression of coronary atherosclerosis. Our results provide additional mechanistic insight into the beneﬁts of beta-blocker therapy in patients with coronary artery disease. Comparison of Beta-blocker and No Beta-Blocker Groups Beta-blocker (n=225) No beta-blocker (n=49) P Age, yrs 57.3±0.7 55.0±1.3 0.14 Male 180 (80%) 35 (71%) 0.19 Hypertension 158 (70.2%) 17 (34.7%) <0.001 Diabetes 38 (16.9%) 9 (18.4%) 0.80 Prior myocardial infarction 77 (34.2%) 17 (34.7%) 0.95 Change in TAV (unadjusted), mm3 0.13±1.57 4.15±3.37 0.28 Change in TAV (adjusted), mm3 -0.61±1.53 7.62±3.40 0.03 957-176 Long-Term Administration of Pioglitazone Reverses Arteriosclerotic Processes in Type-2 Diabetics Tatsuaki Murakami, Hiromasa Kokado, Fukui Cardiovascular Center, Fukui, Japan Introduction and hypothesis: Insulin resistance is thought to be highly involved in arteriosclerotic processes, but the long-term effects of insulin sensitizing agents remain unknown. We assessed hypothesis that long-term use of pioglitazone, an insulin sensitizer, slows ultrasonic manifestation of arteriosclerosis. Methods: Thirty type-2 diabetic patients with suspected coronary artery disease were randomized to group-P where they received pioglitazone (30mg per day) for more than 2 year, or to group-C where they continued therapy without thiazolidinedione for more than 2 year. We noninvasively quantiﬁed intima-media thickness of common carotid artery (IMT) using high-resolution ultrasonography and arterial stiffness by brachial-to-ankle pulse wave velocity (PWV). Changes in IMT and PWV from the baseline through the follow-up point were compared between the 2 groups. Results: Group-P (n=15) manifested good compliance to the treatment and improvements in insulin resistant variables represented by HOMA-IR while group-C showed no improvement (group-P versus group-C: from 2.65± 1.45 to 2.23 ± 1.20, p=0.01, versus, from 2.64 ± 1.29 to 2.66 ± 1.31, p=ns). IMT (mm) decreased in group-P but increased in group-C (group-P versus group-C: from 1.07±0.34 to 1.02±0.36, p=0.03, versus, from 1.07±0.51 to 1.16±0.56, p<0.01). PWV (cm/ sec) decreased in group-P but increased in group-C (group-P versus group-C: 1727±269 to 1644±232, p=0.02, versus, 1710±232 to 1797±215, p=0.03). Changes of IMT or PWV did not correlate to those of HbA1c (IMT: r=0.24, p=0.45, PWV: r=0.14, p=0.83). Conclusions: In conclusion long-term thiazolidinedione use reduces arterial wall thickness and stiffness independent of blood glucose lowering, which may have beneﬁcial potentials for management of arteriosclerosis in type-2 diabetics. 957-177 Effect of Chronic Sildenaﬁl Therapy on Endothelial Function in Diabetic Patients Cristiana Vitale, Maurizio Volterrani, Giuseppe Marazzi, Massimo Fini, Giuseppe M. Rosano, IRCCS San Raffaele, Roma, Italy Background: Phosphodiesterase-5 inhibitors (PDE5) improve erectile dysfunction and endothelial function. Diabetic patients with and without erectile dysfunction have lower response of the endothelium to PDE5 than the general patient population. Aim of this study was to evaluate the effects of chronic therapy with sildenaﬁl (S) on endothelial function in patients with type II diabetes mellitus. Methods: In a double-blind crossover design, 20 patients randomly received a loading dose of S (100 mg) for 3 days followed by either S 25 mg three times a day (tds) for 4 weeks or S 25 mg tds for four days followed by placebo tds for 3 weeks. Endothelial function was evaluated at baseline and at the end of each week of the study by ﬂow mediated dilatation (FMD). Serum levels of NO, endothelin-1, CRP, IL-6, ICAM and VCAM were also measured. Results: After one week FMD improved signiﬁcantly (>50% compared to baseline) in patients allocated to both S arms 62% and 64% respectively. In patients allocated to chronic S a progressive increase in the number of responders was noted (78%, 86%, 94% at 2,3 and 4 weeks respectively) while a progressive decrease in the number of responders was found in the placebo group (45%, 18%, 6% at 2,3 and 4 weeks respectively). At the end of the study a signiﬁcant improvement in FMD compared to baseline were noted in the chronic S group (FMD from 6.8 ± 0.5 to 12.5 ± 0.7%, p=0.01 vs. baseline). A decrease in endothelin-1 levels and an increase in nitrite/nitrate levels were found in the chronic S group, (from 3.6 ± 0.5 to 2.8 ± 0.7 and from 39.1 ± 11.4 to 46.4 ± 7.3, p<0.05, respectively, compared to baseline). In this group signiﬁcant modiﬁcations in CRP, IL-6, ICAM and VCAM levels were also found (-22%, -29%, -18%, -32%, p<0.05, respectively compared to baseline). No changes were observed in the placebo group. Conclusions: Our results demonstrate that in diabetic patients chronic S administration improves endothelial function and reduces the indices of vascular inﬂammation, cronic therapy also increases the number of patients responders to the treatment suggesting that in some patients with type II diabetes there is a marked derangement of endothelial function that may be improved with a long term stimulation. 957-178 Contributions of Endogenous Androgens Versus Age and Waist Circumference to Coronary Plaque and Remodeling in Women: A Report From the NHLBI- Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study B. Clay Sizemore, B. Delia Johnson, Vera Bittner, George Sopko, C. Noel Bairey Merz, Carl J. Pepine, University of Florida, Gainesville, FL Background: Limited work in both the heart transplant population (male patients receiving female donor hearts) and transgender females taking exogenous androgens suggests that female coronaries enlarge when exposed to higher androgen levels. We sought to further clarify the role of endogenous androgens in coronary atherosclerosis and remodeling in women. Methods: A subset of 92 women (mean age 54, 64% post-menopausal), without evidence of angiographic coronary artery disease, underwent intravascular ultrasound (IVUS) at the time of catheterization for suspected ischemia. Serum androgen levels including androstenedione, total testosterone, free testosterone (FT), and sex hormone binding globulin (SHBG) were obtained in 69 of these women. Relationships between these levels and IVUS variables, including mean lumen cross-sectional area (CSA), external elastic membrane (EEM) CSA, and mean atheroma CSA (EEM CSA minus lumen CSA) were assessed by Pearson correlation. Multiple regression modeling was performed to adjust for age and waist circumference. Results: Mean lumen CSA and mean EEM CSA correlated positively with FT (r=0.24, p=0.049 and r=0.29, p=0.01, respectively), and had negative correlations with SHBG (r=-0.26, p=0.03 and r=-0.29, p=0.02). Mean atheroma CSA correlated with FT (r=0.24, p=0.05), age (r=0.45, p=<0.0001), and waist circumference (r=0.36, p=0.003). Waist circumference correlated with EEM CSA (r=0.34, p=0.004), as well as androgens (r=0.39, p=0.004 for FT and r=-0.42, p=0.002 for SHBG). After adjusting for age all relationships between androgens and IVUS parameters remained unchanged, but after adjusting for waist circumference, all relationships became non-signiﬁcant. Conclusions: In women referred for coronary angiography to evaluate suspected ischemia, there are direct relationships between endogenous androgen levels and coronary plaque and remodeling, however, they appear to be primarily driven by waist circumference. 957-179 The Effect of Estrogens on Vascular Reactivity in Women Is Dependent on Aging and Previous Hormone Use Cristiana Vitale, Otavio Gebara, Maurizio Volterrani, Mauricio Wajngarten, Massimo Fini, Giuseppe Marazzi, Giuseppe M. Rosano, IRCCS San Raffaele, Roma, Italy, INCOR, Sao Paulo, Brazil Background: Aging impairs dilator responses of arteries. Natural estrogens (E) improve endothelial function of arteries in post-menopausal women. Whether the effect of E is age-dependent is not known. The aim of the present study was to evaluate: 1)if aging inhibits the beneﬁcial effects of estrogens (E) on vasomotor responses of arteries; 2)if the vasodilator effect of E is related to a previous exposure to estrogen replacement therapy. Methods: we studied endothelial function by means of forearm ﬂow-mediated dilatation (FMD) in 134 postmenopausal women (PMW) aging from 46 to 80 years before and after acute (30 minutes) and chronic (3 months) E administration. Results: At baseline in PMW never estrogen users FMD was inversely associated to time from menopause (r=-0.67, p<0.001) and age (r=-0.43, p<0.05). Multivariate analysis showed time from menopause and age predictors of impaired FMD. Acute and chronic E administration improved FMD (45% and 48% respectively). In PMW who received estrogen replacement therapy in the past acute and chronic E increased FMD more than in PMW who have never been estrogen users (59% and 63% vs 31% and 38%, acute and chronic E respectively, p<0.01) Conclusions: We conclude that: 1) time from menopause more than aging inhibits E effects on endothelium-mediated vascular reactivity of postmenopausal women; 2) past use of ERT reduces the detrimental effect of aging on vascular reactivity and improves the endothelial response to E administration. POSTER SESSION 958 Lipoproteins and Treatment of Atherosclerosis Monday, March 13, 2006, 9:00 a.m.-12:30 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 958-180 Thrombolysis of Massive Pulmonary Embolism: Efﬁcacy and Safety of Adjunctive Therapy With Enoxaparin in Patients Older Than 75 Years Nicolas Meneveau, Vincent Descotes-Genon, Pierre Legalery, Marie-France Seronde, Francois Schiele, Katy Didier-Petit, Florent Briand, Yvette Bernard, Jean-Pierre L. Bassand, University Hospital Jean Minjoz, Besancon, France Background We assessed efﬁcacy and safety of enoxaparin (enox) vs unfractionated heparin (UFH), in combination with thrombolytic therapy (TT) in pts aged >75 years with acute pulmonary embolism (PE). ACC_2006_8_VascularDisease.indd 321 1/4/06 5:21:07 PM 322A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n Methods Prospective, single-centre registry of pts with documented massive or submassive PE, submitted to TT, in the absence of contraindication. In-hospital results included death, recurrent PE, persistent right ventricular (RV) dysfunction at 48h echocardiography and bleeding complications. Results 121 thrombolysed pts were included; 46 treated with UFH (initial bolus of 5000 IU followed by 1000 IU/h infusion)(from 2001-2003); 75 with enox (initial iv bolus of 30mg, followed by 1mg/kg twice daily sc) (from 2003-2005). Clinical and echocardiographic characteristics were similar in both groups. Average age was 80.1±4.1 vs 81.6±4.3, UFH vs enox groups respectively. 23 pts(50%) were hemodynamically unstable in the UFH group vs 44(59%) in the enox group, p=0.46. RV dysfunction was observed in 98% and 99%, UFH vs enox respectively. In-hospital course was uneventful in 63% and 64%, UFH vs enox, p=0.93. Results are described in the table. Conclusion Our data suggest that enox is as safe and effective as UFH in combination with TT in elderly PE pts >75 years. Table UFH(n=46) Enox(n=75) p RV dysfunction at 48h 22 (56.4%) 43 (58.9%) 0.38 Mortality 13 (28%) 12 (16%) 0.17 Recurrent PE 3 (7%) 5 (7%) 0.74 Major bleeds 7 (15.2%) 18 (24%) 0.36 Fatal hemorrhage 2 (4.3%) 2 (2.7%) 0.98 Hemorrhagic stroke 1 (2.2%) 1 (1.3%) 0.70 958-181 Massive Pulmonary Embolism Nils Kucher, Elisa Rossi, Marisa De Rosa, Samuel Z. Goldhaber, University Hospital, Zurich, Switzerland, Brigham and Women`s Hospital, Boston, MA Background: Acute massive pulmonary embolism (PE) carries an exceptionally high mortality rate. We explored how often adjunctive therapies, particularly thrombolysis and inferior vena caval (IVC) ﬁlter placement, were performed and how these therapies affected the clinical outcome of patients with massive PE. Methods: We evaluated 2,392 patients with acute PE and known systolic arterial blood pressure at presentation, from the International Cooperative Pulmonary Embolism Registry: 108 (4.5%) had massive PE, deﬁned as a systolic arterial pressure <90 mm Hg, and 2,284 (94.5%) had non-massive PE with a systolic arterial pressure ≥90 mm Hg. Results: PE was ﬁrst diagnosed at autopsy in 16 (15%) patients with massive PE and in 29 (1%) patients with non-massive PE (p<0.001). The 90-day mortality rates were 52.4% (95% CI 43.3 - 62.1%) and 14.7% (95% CI 13.3 - 16.2%), respectively (log rank p<0.001). In-hospital bleeding complications occurred in 17.6% vs. 9.7%, and recurrent PE within 90 days in 12.0% and 7.5%, respectively (p<0.001). In patients with massive PE, reperfusion therapy, including thrombolysis, surgical, or percutaneous catheter embolectomy, was withheld in 73 (68%). Thrombolysis was performed in 33 patients, surgical embolectomy in 3, and catheter embolectomy in 1. Thrombolytic therapy did not reduce 90-day mortality (HR 0.79, 95% CI 0.44 - 1.43; p = 0.44). Recurrent PE rates at 90 days were similar in patients with and without thrombolytic therapy (12% for both; p =0.99). None of the 11 patients who received an IVC ﬁlter developed recurrent PE within 90 days, and 10 (90.9%) survived at least 90 days. IVC ﬁlters were associated with a reduction in 90-day mortality (HR 0.12, 95% CI 0.02 - 0.85; p =0.002). Conclusions: In ICOPER, two thirds of the patients with massive PE did not receive reperfusion therapy. Counterintuitively, thrombolysis did not reduce mortality or recurrent PE at 90 days. The observed reduction in mortality from IVC ﬁlters requires further investigation. 958-182 Prognostic Signiﬁcance of Inverted T Waves in Patients With Acute Pulmonary Embolism Masami Kosuge, Kazuo Kimura, Toshiyuki Ishikawa, Toshiaki Ebina, Kiyoshi Hibi, Kengo Tsukahara, Masahiko Kanna, Satoshi Umemura, Yokohama City University Medical Cente, Yokohama, Japan Background: Inverted T waves are a common ECG ﬁnding in acute pulmonary embolism (PE), but their clinical signiﬁcance remains unclear. The purpose of this study was to evaluate the clinical utility of inverted T waves to identify high-risk patients with acute PE. Methods: We studied the relation of the number of leads with inverted T waves to the severity of PE in 40 patients (mean age 63 years, 15 men and 25 women) with acute PE. PE was conﬁrmed by pulmonary arterial angiography, lung perfusion scintigraphy, or spiral computed tomography scan. A 12-lead ECG was recorded on admission. An inverted T wave was considered present if the depth was >0.5mm in any lead except lead aVR. Patients were classiﬁed into 3 groups according to the number of leads with inverted T waves on admission ECG: 15 patients, <3 leads (G-L); 12 patients, 4 to 6 leads (G-M); and 13 patients, >7 leads (G-H). Results: In G-L, G-M, and G-H, the incidence of right ventricular dysfunction on echocardiography was 47%, 92%, and 100% (p<0.01), mean pulmonary artery pressure during the acute phase was 26, 31, and 38mmHg (p<0.01), and in-hospital complicated events including death, need for catecholamine support, cardiopulmonary resurscitation, or mechanical cardiovascular support because of hemodynamic instability was 0%, 8%, and 46% (p=0.004), respectively. There were no differences among the 3 groups with regard to arrhythmia, pulmonary P, right axis deviation, right bundle branch block, S1S2S3, low voltage, right ventricular hypertrophy, ST elevation or ST depression. There was a slightly but not signiﬁcantly higher incidence of S1Q3T3 in G-H. Left axis deviation was observed in only G-H. G-H had the highest incidence of clockwise rotation. In the multivariate models, arterial hypotention at presentation (odds ratio 8.96, 95% CI 1.09 to 119.5, p=0.049) and inverted T waves in >7 leads (odds ratio 16.8, 95% CI 1.17 to 212.8, p=0.037) were the only independent predictors of in-hospital complicated events; the other ECG ﬁnding on admission ECG was not. Conclusions: The number of leads with inverted T waves on admission ECG may be a useful and simple marker of increased risk for early complications in patients with acute PE. 958-183 Total Circulating and Platelet Microparticles Are Elevated in Acute Pulmonary Embolism Stephane Ederhy, Emanuele Diangelantonio, Laurence Bal, Benedicte Hugel, Sandra Janower, Catherine Meuleman, Franck Boccara, Jean-Marie Freyssinet, Ariel Cohen, Hopital Saint Antoine, Paris, France, Universite Pierre et Marie Curie, Paris, France Background Thrombus formation and propagation in venous thromboembolism depend on the presence of abnormalities in blood ﬂow, vessel wall and clotting components. Total circulating microparticles (TMP), and subtypes, endothelial (EMP) and platelet (PMP), constitute a relevant marker of cellular damage and activation, and have been reported to be elevated in clinical situations at increased risk of arterial thrombosis. Based on a case-control design, we investigated whether TMP, EMP and PMP would be increased in acute pulmonary embolism (PE). Methods TMP, EMP and PMP levels were measured in 47 consecutive patients (68.9 ± 13.5y, male 36.2 %) admitted in an intensive care unit for acute PE and in 25 healthy control subjects with no previous history of venous thrombo embolism and no vascular risk factors. PE was diagnosed by spiral computed tomography or ventilation perfusion scintigraphy. MPS levels were assessed by a prothrombinase assay on a platelet depleted plasma and results were expressed as nmol/L equivalent. Annexin V immobilized TMP were captured by speciﬁc antibodies to determine their cells origin with anti GP1B for platelet (PMP) and anti CD31 for endothelial MP origin (EMP). Results TMP levels (nmol/l) were higher in PE patients (median 4.1, Interquartile Range, IQR=2.6-6.6) than in controls (median 2.8, IQR 2-4.2; p=0.012). PMP levels were elevated also in PE patients (median 2.3, IQR 1.7-5.4) when compared to controls (median 1.9, IQR 1.3-2.1; p=0.007). EMP levels were not signiﬁcantly different in PE patients and in controls (median 0.01, IQR 0.01-0.2 and 0.01, IQR 0.01-0.1 respectively) (p=0.293). Since the values of MP in the linear regression analysis analysis were not normally distributed, they were examined after logarithmic transformation (log). In multivariate analysis and after adjusting for potential confounders, the independent determinants of logTMP were hypertension 0.35 (95%CI -0.003 to 0.71, p=0.052) and PE 0.41 (95%CI 0.09 to 0.74, p=0.014). Conclusion Total circulating microparticles and platelet microparticles are elevated in acute PE. Platelet microparticles appeared to be the main source of procoagulant MP release observed in acute PE. 958-184 Monitoring of Patients With Conﬁrmed Pulmonary Embolism Using NT-pro-Brain Natriuretic Peptide and Cardiac Troponin T Susanne Korff, Margit Mueller-Bardorff, Britta Weidtmann, Volkhard Kurowski, Uwe Weigand, Hugo A. Katus, Evangelos Giannitsis, University of Heidelberg, Heidelberg, Germany, University of Luebeck, Luebeck, Germany Background: Recent studies have established the role of cardiac troponin T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) for risk stratiﬁcation in patients with acute pulmonary embolism (PE). The purpose of this study was to evaluate the utility of NT-proBNP and cTnT for monitoring of the clinical course and success of therapy in PE. Methods: We studied 39 patients with angiographically conﬁrmed PE of whom 18 received thrombolysis as an adjunctive therapy. Pulmonary artery pressure was monitored in all patients. A mean of 6 samples for NT-proBNP and 5 samples for cTnT were determined serially and were plotted against clinical course and treatment. Results: Peak NT-proBNP and cTnT values correlated highly signiﬁcant with severity of PE according to Goldhaber classiﬁcation (p = 0.004, r = 0.498 and p = 0.003, r = 0.502 respectively). Individual time release curves of NT-proBNP and cTnT allowed to distinguish between patients with failure of thrombolysis or adverse clinical outcome and those with resolution of pulmonary hypertension or uncomplicated course. Conclusions: NT-proBNP and cTnT correlate with right heart strain and clinical severity of pulmonary embolism. Our data demonstrate that NT-proBNP and cTnT could be useful for non-invasive assessment or right ventricular afterload, thereby identifying individuals with successful or failed conservative or thrombolytic therapy. 958-185 Computer Alert Increases Use of Prophylaxis for Patients at High Venous Thromboembolism Risk John Fanikos, Jennifer Cina, Marilyn Paterno, Steven Baroletti, Samuel Z. Goldhaber, Brigham and Women’s Hospital, Boston, MA A computer program identiﬁed hospitalized patients at high risk for venous thromboembolism (VTE), alerted physicians to prescribe prophylaxis, and reduced VTE events by 41% [NEJM 2005;352:969]. We performed a cohort study to determine whether VTE prophylaxis prescribing changed following study publication. Methods The computer calculated VTE risk scores based upon 8 common VTE risk factors, each weighted according to a point scale. “High risk” was deﬁned as > 4 score points. Major risk factors (cancer, prior VTE, and hypercoagulability) each scored 3 points, major surgery 2 points, and age, obesity, bed rest, and hormone therapy scored 1 point each. When no prophylaxis was prescribed, the physician was alerted electronically. We compared response to alerts following study publication to those in the intervention group of our randomized trial. Results Among high risk hospitalized patients, overall VTE prophylaxis increased from 82% to 93% (p<0.001) (Table). Most high risk patients not receiving prophylaxis were Medical Service patients (80%). Physicians responded to the alert by prescribing prophylaxis in 40% in the cohort compared with 34% of historical controls (p=0.01). More cohort patients (14%) received mechanical prophylaxis than historical controls (p=0.03). Conclusions Most high VTE risk patients not receiving prophylaxis are Medical Service patients. An electronic alert, tailored to detect high VTE risk patients not receiving prophylaxis can increase utilization of VTE prophylaxis. ACC_2006_8_VascularDisease.indd 322 1/4/06 5:21:08 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 323A Vascular D isease, H ypertension, and P revention Cohort Comparison of VTE Porphylaxis Present Cohort n (%) Historical Control n (%) p Patients at risk of VTE without VTE prophylaxis 411 (7%) 1255 (18%) p<0.001 Medical Patients Surgical Patients 330 (80) 81 (19) 1038 (82) 217 (17) p=0.3 p=0.3 Patients with Cumulative Risk Score of 4 266 (64) 792 (63) p=.60 Patients with Cumulative Risk Score of 5 101 (24) 327 (26) p=.60 Patients with Cumulative Risk Score of 6 37 (9) 110 (8) p=.96 Patients with Cumulative Risk Score of 7 or > 7 (1) 26 (1.3) p=.57 Prophylaxis Prescribed 166 (40) 421 (34) p=.01 Pharmacologic 80 (20) 296 (24) p=.10 Mechanical 58 (14) 125 (10) p=.03 POSTER SESSION 959 Markers in Heart Failure and CAD Monday, March 13, 2006, 9:00 a.m.-12:30 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 959-186 Acute Coronary Syndromes Do Not Lower Lipid Levels Bertram Pitt, Joseph Loscalzo, Joseph Ycas, Joel Raichlen, LUNAR Study Group, University of Michigan School of Medicine, Ann Arbor, MI, AstraZeneca, Wilmington, DE Background Previous studies had indicated that cholesterol levels fall signiﬁcantly after acute coronary syndromes (ACS). However, most studies were small and calculated low-density lipoprotein cholesterol (LDL-C) indirectly, and many used non-fasting or retrospective data, often with great variability. More recent publications suggest a smaller LDL-C fall than earlier reports. Data from the LUNAR trial (Limiting UndertreatmeNt of ACS with Rosuvastatin) allowed critical assessment of these ﬁndings. Methods LUNAR is a 12-week, randomized, multicenter study to compare efﬁcacy and safety of rosuvastatin 20 mg and 40 mg with atorvastatin 80 mg in modifying lipids and inﬂammatory and thrombotic markers in ACS. LDL-C levels were directly measured within 48 hours of onset of ACS symptoms (median 25 hours post onset [Day 1]), after overnight fast (median 40 hours post onset [Day 2]), and before randomization (median 83 hours post onset [Day 4]). Results The study had 305 patients with LDL-C measurements at all 3 time points. The table shows mean LDL-C values. No clinically signiﬁcant changes in LDL-C were observed at any time point. Similar results were observed for patients presenting with unstable angina, ST elevation (STE) MI, and non-STE MI. Conclusion In contrast to accepted beliefs, these data show LDL-C does not fall between Day 1 and Day 4 after onset of symptoms in patients with ACS. Thus, measurements of lipids during this time are valid for clinical decisions about lipid lowering therapy. N LDL-C Day 1 (mg/dL) Mean + SD LDL-C Day 2 (mg/dL) Mean + SD LDL-C Day 4 (mg/dL) Mean + SD % Change Day 4 vs Day 1 Mean + SE All ACS 305 138 ± 32 134 ± 33 141± 34 + 3.2 + 1.27 Unstable angina 88 139 ± 33 138 ± 34 144 ± 36 + 4.8+ 2.22 MI 217 137± 31 132 ± 32 139 ± 34 + 2.5 + 1.53 STE 104 138 ± 32 134 ± 34 142 ± 35 + 4.4+ 2.31 Non-STE 113 136 ± 30 130 ± 30 137 + 32 +0.9 + 2.04 959-187 Oral Nicorandil Improves Clinical Outcomes After Coronary Angioplasty in Patients With Renal Failure on Hemodialysis Hideki Ishii, Takanobu Toriyama, Toru Aoyama, Hiroshi Takahashi, Masayuki Torigoe, Tetsuya Amano, Tatsuaki Matsubara, Toyoaki Murohara, Nagoya University Graduate School of Medicine, Nagoya, Japan, Nagoya Kyoritsu Hospital, Nagoya, Japan Background: Patients with renal failure on hemodialysis (HD) are at high risk for death with ischemic heart disease. On the other hand, nicorandil, a hybrid compound of ATP-sensitive potassium channel opener and nitric oxide donor, has been reported to improve clinical prognosis in patients with ischemic heart disease. The purpose of this retrospective study was to investigate the long-term effects of oral nicorandil in patients with renal failure on HD, who underwent percutaneous coronary intervention (PCI) due to angina pectoris (AP). Methods: A total of 356 patients on HD undergoing PCI for AP were enrolled. They were divided into the two groups; patients received 15 mg nicorandil three times daily in conjunction with standard therapy (n = 198) and patients without nicorandil (n = 158). We analyzed incidence of coronary heart disease death, non-fatal myocardial infarction and unplanned hospital admission for worsening cardiac chest pain as well as all cause death. Results: Baseline characteristics were similar in both groups. Upon Kaplan-Meier analysis, the frequency of cardiac events was signiﬁcantly lower in patients on nicorandil (hazard ratio = 0.68, 95% CI = 0.49-0.94, p = 0.018). Furthermore, in patients with diabetes mellitus, nicorandil had much better effects on preventing cardiac events (hazard ratio = 0.56, 95% CI = 0.38-0.84, p = 0.0055). However, all cause mortality was not signiﬁcantly different between two groups (hazard ratio = 0.76, 95% CI = 0.44-1.31, p = 0.31). Conclusions: Nicorandil treatment was associated with a signiﬁcant improvement in outcome after PCI in dialysis patients with ischemic heart disease. The addition of oral nicorandil to standard therapy may be a useful strategy even for patients with renal failure on HD, that is, with a surrounding high risk for death with ischemic heart disease. 959-188 Sex Differences in the Inﬂammatory Response to Leptin: Results From the Dallas Heart Study Shuaib M. Abdullah, Amit Khera, Sandeep R. Das, David Leonard, Russell M. Canham, Sandeep A. Kamath, Gloria Vega, Scott M. Grundy, Darren K. McGuire, James A. de Lemos, University of Texas Southwestern, Dallas, TX Background: Inﬂammation is an important contributor to the association between obesity and cardiovascular disease, but the mechanisms linking obesity with inﬂammation are not known. We explored the association between the adipokine, leptin, and C-reactive protein (CRP) in men and women in the general population. Methods: Total body fat was measured by dual energy X-ray absorptometry, and plasma leptin (Linco Research Inc.) and CRP (Roche/Hitachi 912 System, Tina-quant CRP high sensitive assay, Roche Diagnostics, Indianapolis, IN) levels were measured in 1250 women and 1212 men from the Dallas Heart Study, a probability-based population sample, excluding those taking statins or estrogen. Analyses were stratiﬁed by sex, and leptin was indexed to total fat mass to evaluate its association with CRP independent of adiposity. Results: Median plasma levels of CRP and leptin were higher in women compared with men (CRP 3.3mg/L vs 1.9mg/L, p< 0.0001; leptin 22.7 µg/L vs 5.4 µg/L, p<0.0001), and were associated with higher body mass index (BMI) and total fat mass in both sexes. A signiﬁcant correlation was present between CRP and leptin levels in women (Spearman ρ=0.48, p<0.0001) and in men (ρ=0.27, p<0.0001). Median CRP levels increased across increasing quartiles of leptin indexed to fat mass in both sexes. (women ptrend<0.0001; men ptrend =0.002) In multivariable analyses adjusting for BMI, hypertension, diabetes, low HDL, hypercholesterolemia, tobacco use, alcohol use, age and race, leptin (indexed to fat mass) remained signiﬁcantly associated with log CRP in women (p<0.001), but not in men (p=0.50). A signiﬁcant interaction was detected between leptin and sex on CRP levels (p=0.01). Substituting total fat mass for BMI did not change the results in either sex. Conclusions: Leptin was associated with CRP independent of other markers of obesity in women, but not in men. These ﬁndings suggest that higher CRP levels seen in women versus men may be partially explained by both higher leptin levels and by a qualitatively greater inﬂuence of leptin on CRP production in women, and highlight potentially important sex-related differences in the inﬂammatory responses to obesity. 959-189 Beneﬁcial Effects of Dual Angiotensin-II Suppression With ACE-inhibitor and Angiotensin Receptor Blocker on BNP, CRP and Glucose Regulation in Patients With Symptomatic Heart Failure Michel White, Serge Lepage, Joël Lavoie, Simon de Denus, Marie-Hélène LeBlanc, Denis Gossard, Normand Racine, Anique Ducharme, Lucette Whittom, Jean-Lucien Rouleau, Rhian Touyz, Montreal Heart Institute, Montreal, PQ, Canada The addition of an angiotensin receptor blocker (ARB) to an ACE inhibitor decrease morbidity and mortality in patients with symptomatic heart failure (HF). The effects of the ARB Candesartan on BNP, high sensitivity (hs) CRP, selected markers of inﬂammation and glucose regulation in a cohort of patients with a high proportion of beta-blocker therapy have not been investigated. Methods: Eighty patients with symptomatic HF aged 62.5±8.4 years (mean±SD) presenting mostly NYHA class II symptoms (class II=57.5%, III=41.3%), LV ejection fraction of 27.1±7.3% were recruited. The patients were randomized to receive Candesartan titrated to 32 mg o.d. vs. placebo in double-blind fashion for 6 months. Forty-seven percent of the patients presented with either glucose intolerance (24%) or diabetes (23%). All patients were treated with an ACE inhibitor and 94% received a beta- blocker. Blood samples for N-terminal pro-BNP, hsCRP, selected markers of inﬂammation and oxidative stress, glucose, insulin and fasting insulin resistance index (FIRI) were analyzed. Selected results are presented in the table. Conclusions: The addition of Candesartan to ACE inhibitor and beta-blocker therapy decreases BNP and CRP in patients with well-compensated CHF. Dual angiotensin-II suppression decrease blood glucose with a greater impact in patients with higher baseline blood glucose. The mechanisms involved require additional investigations. SBP (mmHg) NT-proBNP (ng/L) hsCRP (mg/L) Glucose (mmol/L) Insulin (pmol/L) FIRI (units) Placebo BSL 113±20 1126±993 5.70±7.53 7.88±1.96 147±84 6.68±4.04 6 m 113±17 1218±1380 7.58±14.9 8.16±2.57 156±88 8.12±6.32 Candesartan BSL 108±14 1844±2750 6.90±13.50 9.10±2.94 191±274 12.1±23.6 6 m 104±16† 1644±3043† 5.30±8.66† 7.52±2.50†‡ 274±472 6.21±5.72 Data are mean ± SD; †P≤0.05 vs placebo; ‡P<0.01 for the interaction for baseline blood glucose. ACC_2006_8_VascularDisease.indd 323 1/4/06 5:21:09 PM 324A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n 959-190 The Impact of Treatment With Levosimendan or Dobutamine on Brain Natriuretic Peptide Levels in Patients With Acutely Decompensated Chronic Heart Failure. Results From the Calcium Sensitizer or Other Inotrope or None in Acutely Decompensated CHF (CASINO) Study Michael N. Zairis, Charalampos Apostolatos, Anastassios Theodosis-Georgilas, Stamatis Makrygiannis, Pelagia Batika-Zairi, Demetrios Billias, Paraskevi Psarogianni, Konstantinos Mainas, Markos Glyptis, Nikolaos Tellis, Demetrios Beldekos, Stefanos G. Foussas, Tzanio Hospital, Piraeus, Greece Background-We investigated the impact of treatment with levosimendan, or dobutamine on the course of BNP levels in pts enrolled in the CASINO study. Methods-The CASINO was a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study which investigated the hypothesis that a 24-hr treatment with levosimendan would result in better survival than treatment with either placebo or dobutamine, in 299 patients who were hospitalized for acutely decompensated (NYHA class IV) low-output CHF. Venous blood samples were obtained upon randomization as well as 8; 16; 24 and 48 hrs later. Results-There were no signiﬁcant differences in baseline characteristics and the serum BNP levels (p=0.9) upon randomization among the patients assigned to levosimendan, dobutamine, or placebo. The mean BNP levels decreased signiﬁcantly from randomization through 48 hrs in all study groups. There was no difference in the the decrease in BNP levels between patients assigned to dobutamine or placebo throughout the study period of 48 hrs. However, pts assigned to levosimendan had signiﬁcantly greater decrease in BNP levels than those assigned to dobutamine (p<0.05 for all time points) or placebo (p<0.05 for all time points) (Figure). Conclusions-The present results have shown that treatment with levosimendan but not with dobutamine induces a signiﬁcantly greater decrease in BNP levels than treatment with placebo early in the ﬁrst 48 hrs of acute decompensation of severe low-output CHF. 959-191 Risk Prediction With Cardiac Troponin T Versus Biochemical Markers Associated With Cardiac Remodeling Yukiko Nishio, Yukihito Sato, Takeshi Kimura, Toru Kita, Graduate School of Medicine, Kyoto University, Kyoto, Japan Background: Several pathologic processes can cause myocardial injury, followed by cardiac remodeling, congestive heart failure (CHF) and ventricular tachyarrhythmias (VTA). Cardiac troponin T (cTnT), a speciﬁc and sensitive marker of myocardial injury, has been related to long-term outcome in patients with CHF. We have studied the relationship between cTnT and other biochemical markers associated with cardiac remodeling. Methods: Between February 2004 and July 2005, 132 consecutive hospitalized patients (mean left ventricular ejection fraction = 38.9±1.4%) with stable or unstable CHF or VTA were divided into a low (<0.01 ng/ml) and a high (>0.01 ng/ml) serum cTnT group. Correlations with other biochemical markers, including brain natriuretic peptide (BNP), type I collagen C-terminal telopeptide (ICTP), procollagen typeIII peptide (PIIIP), type IV collagen 7S domain (IV7S), norepinephrine (NOREPI), C-reactive protein (CRP) and renin, were examined. Results: cTnT was high in 44 (33%) and low in 88 (67%) patients at baseline. Patients with high cTnT had abnormally high blood concentrations of BNP (P <0.0001), ICTP (P <0.0001), IV7S (P <0.05), renin (P=0.009), NOREPI (P <0.05), and CRP (P=0.007), hemoglobin A1c (HbA1c)(P=0.0081), creatinine (P=0.0492) and uric acid (P=0.0064) . Sudden or non-sudden cardiac deaths, or rehospitalization for CHF or life-threatening VTA occurred in 39% in the high versus 13% in the low cTnT group (P=0.0012). By multivariate analysis, cTnT, BNP, ICTP, IV7S, NOREPI, CRP, cholesterol, hemoglobin, creatinine and LVEF were independent predictors of major adverse cardiac events, and PIIIP, ICTP and BNP were independent predictors of VTA. Conclusions: Patients with ongoing myocardial injury and high cTnT had associated ﬁndings consistent with activation of the sympathetic and renin-angiotensin systems, synthesis of cardiac ﬁbrosis, and inﬂammation. cTnT had additive prognostic value in patients with CHF. And also these observations suggest that collagen may be a marker of sudden death due to ventricular arrhythmias. POSTER SESSION 960 Hypertension: Genetics and Populations Monday, March 13, 2006, 9:00 a.m.-12:30 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 960-192 Angiotensin Converting Enzyme (ACE) Polymorphism, Albuminuria, and Systemic Capillary Permeability in Hypertensive Men Giulia Dell’Omo, Giuseppe Penno, Laura Pucci, Carmen Fotino, Stefano Del Prato, Roberto Pedrinelli, Università di Pisa, Pisa, Italy BACKGROUND: A DD polymorphism within the ACE gene exposes to an increased risk of microalbuminuria (MA), a marker of preclinical renal damage, and atherosclerotic vascular disease in essential hypertension. To understand to a deeper extent the pathophysiological mechanisms of that association, we hypothesized an impact of DD genotype on systemic capillary permeability to macromolecules, a critical control mechanism for the atherogenic process. MATERIALS&METHODS: The ACE gene polymorphism was determined by PCR using DNA extracted from blood samples. Urinary albumin excretion (UAE, by nephelometry, the mean of 3 consecutive overnight collections), transcapillary escape rate of albumin (TERalb, the 1-hour decline rate of intravenous 125I-albumin, a measure of the integrity of systemic capillary permeability), 24-hr BP, serum creatinine, lipids, fasting glucose, insulin and HOMA as an index of insulin sensitivity, BMI and lipids were measured in 80 never treated, uncomplicated hypertensive men. Analyses were carried out by comparing DD homozygotes (49±11yrs, n=36) vs ID/II (48±9 yrs, n=44) subjects grouped together. RESULTS: UAE [11 (2-72.3) vs 8 (2-39.9) µg/min, p=0.03) and TERAlb (10.4±2.7 vs 9.2±2.7, p=0.03) were higher in DD than ID/II pts and the two parameters were associated intraindividually (r=0.27, p=0.018, n=80). MA (UAE≥15 µg/min) was more frequent in the former subgroup (68% vs 37%, p=0.03). 24-hr BP (136±14/ 88±8 vs 138±17/88±10 mmHg), fasting glucose (96±11 vs 100±11 mg/dl), insulin (14±13 vs 15.5±9 µU/ml), HOMA index (3.4± 4.2 vs 3.9± 2.4), serum creatinine (1.1±0.2 vs 1.0±0.2 mg/dl) and lipids did not differ between the two groups. CONCLUSIONS: The ACE DD genotype is associated with higher UAE and TERalb independent of BP levels and several other potentially confounding factors in mild- moderate essential hypertensive men. The association of the ACE DD genotype with subclinical renal damage may reﬂect a parallel noxious inﬂuence on systemic vascular permeability, contributing to accelerate the atherogenic process. 960-193 Ace Gene Copies Number Impairs Hemodynamic Responses to Hypertension in Mice Alexandre Ceroni, Edson D. Moreira, Vera L. Oliveira, Eduardo M. Krieger, Maria Cláudia C. Irigoyen, Heart Institute of São Paulo University - Medical School, São Paulo, Brazil BACKGROUND: Clinical and experimental evidence suggests that renovascular hypertension is partially mediated by the activation of renin angiotensin system. We investigated the effect of angiotensin-converting enzyme (ACE) gene copies on blood pressure (BP), baroreﬂex sensitivity (BRS) and cardiac hypertrophy in two-kidney, one- clip hypertensive mice. METHODS AND RESULTS: Male Mice harboring 2, or 3 copies of the ACE gene were studied 4 weeks after left renal artery clipping (groups 2CC and 3CC) or sham surgery (2C and 3C). Blood pressure signals were recorded in conscious animals using a data acquisition system (CODAS, 4 kHz). BRS was evaluated by the tachycardic (TR) and bradycardic (BR) reﬂex responses to arterial pressure changes induced by increasing doses of sodium nitroprusside and phenylephrine. ACE activity was quantiﬁed by ﬂuorimetric measurements. Changes in ACE gene copies did not alter BP values in controls (2C: 106±3; 3C: 106±3 mmHg), but induced greater BP response to renal clipping (129±1 and 153±2,6 mmHg in 2CC and 3CC, respectively). No changes were observed in basal heart rate between all groups. The BRS to BR were depressed in both, 2CC (40%) and 3CC (60%) when compared with 2C and 3C (3± 0.2 and 3.1±0.6 bpm/mmHg, respectively) but the attenuation was larger in 3CC. Similar impairment was observed for TR in 2CC (20%) and 3CC (45%) as compared with 2C and 3C (1.3±0.7 and 2.2±0.6bpm/mmHg, respectively). Similarly to observed in BR, the attenuation in TR was larger in 3CC. The LV weight/body weight ratio increased in 3CC mice (5.2±0.5 mg/Kg) when compared with other groups: 2CC (3.2±0.2 mg/Kg), 3C (3±0.1mg/Kg) and 2C groups (3±0.05 mg/Kg). Serum ACE activity was similar in 2C and 3C mice (22 vs. 21 x10-3 uF/min/µl) but increased 10 times in 2CC and 20 times in 3CC. CONCLUSIONS: Although hemodynamic parameters were unaffected by ACE genotype at baseline, the present results provide evidence that the number of ACE gene copies inﬂuence the development of renovascular hypertension and cardiac hypertrophy in mice. 960-194 Investigation of Genetic and Biochemical Determinants of Depressed L-Arginine Transport in Human Hypertension Zhiyong Yang, Brian J. Morris, David M. Kaye, Baker Heart Research Institute, Melbourne, Australia, University of Sydney, Sydney, Australia Background: Endothelial dysfunction due to reduced nitric oxide (NO) bioavailability is a cardinal feature of essential hypertension (EH) and several mechanisms have been proposed. Recently we demonstrated that this might be due to decreased endothelial uptake of the nitric oxide precursor, L-arginine, while others have proposed a role for the nitric oxide synthase (NOS) inhibitor, asymmetric dimethyl L-arginine (ADMA). Given that EH shows a ACC_2006_8_VascularDisease.indd 324 1/4/06 5:21:09 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 325A Vascular D isease, H ypertension, and P revention signiﬁcant familial link, we tested the hypothesis that a genetically determined impairment of L-arginine uptake, via the arginine transporter CAT-1, may occur in EH. In conjunction we aimed to exclude ADMA as a signiﬁcant inhibitor of arginine uptake in man. Methods: We sequenced the entire CAT1 gene and identiﬁed a novel C/T polymorphism in the 3’UTR region of the CAT1 gene. Subsequently, we determined the genotype of 407 healthy subjects and 285 hypertensives. In conjunction, we assessed forearm L- arginine uptake during an intra-arterial infusion of [3H]L-arginine, endothelial function and measured the plasma concentration of arginine and ADMA 10 young patients with EH and 14 healthy control subjects. Results: In control subjects the frequency of the TT genotype was 0.3% while in EH it was 1.8% (p<0.05). The biological effect of the 3’UTR polymorphism, was conﬁrmed by luciferase reporter assays which showed that the presence of the T allele was accompanied by signiﬁcantly lower luciferase activity (p<0.05). In keeping with previous ﬁndings, L-arginine uptake was substantially reduced in EH (p<0.01), and while plasma ADMA concentration tended to be elevated in EH (p=0.065), the decrease in arginine transport did not correlate with ADMA levels. Conclusions: We have identiﬁed a novel polymorphism in the CAT1 gene, which may contribute to the pathophysiology of hypertension. 960-195 Do Loss-of-Function Mutations in Alpha 2 Adrenergic Receptor Subtypes Predispose to Hypertension in Blacks? Population-Level Data From the Dallas Heart Study Russell M. Canham, Jia-Ling Li Li, David Leonard, Wanpen Vongpatanasin, Richard J. Auchus, Ronald G. Victor, UT - Southwestern Medical Center, Dallas, TX, Donald W. Reynolds Cardiovascular Clinical Research Center Background: Sequence variations in α2 adrenergic receptor (AR) genes have been implicated as a cause of neurogenic hypertension and hypertensive heart disease in Blacks. Although certain allelic variations in α2A receptor subtypes are selectively enriched in Blacks, their association with increased blood pressure is based on small non-random samples that have not been conﬁrmed in larger populations. Methods: In a stratiﬁed random population sample of 1,766 Blacks 30 to 65 years of age, we examined the strength of association between blood pressure (ten in-home measurements with an accurate electronic monitor) and hypertensive heart disease (cardiac MRI) with two sequence variations: 1) a Dral restriction fragment length polymorphism in the α2A AR that seems to decrease adrenergic receptor number and thus α2 AR restraint on central sympathetic outﬂow, and 2) a four amino-acid deletion in the α2C AR (α2C Del 322-325) that impairs feedback inhibition of norepinephrine release from peripheral sympathetic nerve terminals. Important environmental covariates were assessed with an extensive in-home health interview conducted by ethnically-congruent surveyors. Results: In this Black population sample, we conﬁrmed that allele frequencies for the mutant α2A and α2C receptors were .50 and .61, respectively. The major new ﬁnding is that neither hypertension nor any of the cardiac MRI parameters varied by genotype: the unadjusted prevalence of hypertension was 42% regardless of genotype. In a logistic model that controlled for age, BMI, diabetes, and smoking, the adjusted odds ratio for hypertension was 0.9 (95% CI 0.7, 1.1) with the α2A mutation and 1.0 (95% CI 0.8, 1.3) for the α2C mutation. In the subset of untreated subjects, neither of these mutations alone or in combination was predictive of blood pressure, heart rate, left ventricular mass, cardiac output, systemic vascular resistance, or aortic compliance. Conclusions: In the largest and only population-based study of these polymorphisms to date, we found no evidence to support the attractive hypothesis that loss-of-function mutations in either the α2A AR or α2C AR (Del 322-325) constitute important candidate genes for hypertension in Blacks. 960-196 Endothelial Nitric Oxide Synthase Glu298asp Gene Polymorphism Is Associated With Hypertensive Response to Exercise in Well-controlled Hypertensive Patients Jung-Sun Kim, Sungha Park, Chanmi Park Park, Young-Guk Ko, Donghoon Choi, Hyun-Young Park, Yangsoo Jang, Namsik Chung, Yonsei Cardiovascular Center, Yonsei University College of Medicine, Seoul, South Korea, National Institute of Health, Seoul, South Korea Background Hypertensive response to exercise (HRE) is known to be an adverse prognostic factor for cardiovascular events in the future. Endothelial dysfunction during exercise may be important in the pathogenesis of hypertensive response to exercise. Previous studies done regarding endothelial nitric oxide synthase (e-NOS) Glu298Asp (E/D) gene polymorphism focused upon its relation to hypertension. In this study, we hypothesize that the polymorphism may be associated with inherent difference in endothelial response to exercise. Therefore we investigated the association of e-NOS Glu298Asp gene polymorphism with HRE. Method Two hundred seventy patients with well-controlled, essential hypertension (BP < 160/100mmHg) who underwent treadmil test were enrolled in this study; 77 patients (mean age 55.8±9.4 years) had hypertensive response, deﬁned as peak systolic BP of ≥210mmHg in men and ≥190mmHg in women and 193 patients (mean age: 53.9±8.8 years) had absence of hypertensive response. The e-NOS E298D exchange (G894T) in exon 7 was determined by the methods of single base extension with amplifying primers and probes for TaqMan. Result The percentages of the EE298 (GG), ED298 (GT) and DD298 (TT) genotypes were 81.1, 18.5, 0.4 %, respectively. The presence of GT or TT genotype, assuming co-dominant effect of the T allele, was independently associated with prevention of hypertensive response when controlled for age, sex, baseline systolic blood pressure and HOMA index [OR=0.35(0.14-0.82), P-value = 0.016]. Subgroup analysis showed that this effect was signiﬁcant in females but not in males, with female patients with GT or TT genotype demonstrating absence of hypertensive response with signiﬁcantly lower increment of systolic blood pressure response during exercise compared to the GG genotype (48.8±23.3 vs. 34.4±13.0, p < 0.001). Conclusion In our study, e-NOS E298D gene polymorphism was signiﬁcantly associated with hypertensive response to exercise in well-controlled hypertension. This result suggests that the presence of T allele of the E298D polymorphism may be a favorable factor to in preventing HRE, especially in female patients. 960-197 Association Between Refractory Hypertension and Endothelial Nitric Oxide Synthase -786C allele Ignacio Cruz, Javier Martin Moreiras, Maria Sanchez-Ledesma, Esther Corral, David Varillas, Jesus Herrero-Garibi, Maria Jose Ruiz, Angel Sanchez-Rodriguez, Rogelio Gonzalez-Sarmiento, Candido Martin Luengo, Universitary Hospital of Salamanca, Salamanca, Spain, Molecular Medicine Unit. University of Salamanca, Salamanca, Spain Background: Recent clinical trials suggest that refractory hypertension is increasingly common. It is estimated that 5% of the hypertensive patients are resistant to conventional antihypertensive therapy. Genetic factors contribute to the pathogenesis of essential hypertension, and could explain the differences in response to the treatment. Polymorphisms in endothelial genes, as Pro12Ala in the Peroxisome proliferator-activated receptor gamma 2 (PPARG) or Glu298Asp and the T-786>C in the endothelial nitric oxide synthase (NOS3), have been associated with high blood pressure levels, but not with refractory hypertension. Methods:We perfomed a prospective case-control observational study. We found 50 patients with refractory hypertension from a serie of 950 consecutive patients controlled at a Hypertension Unit and followed up during 42 months. We estimated the sample size (conﬁdence interval 95%, power 80%) and we selected 236 sex and aged-matched patients with controlled high blood pressure. The Pro12Ala variant of the PPARG, as well as the Glu298Asp and the T-786>C polymorphism of the NOS3, were genotyped by polymerase chain reaction and restriction endonuclease digestion. The chi-square statistics was used to test the signiﬁcance of any association between genotype or alelle distribution and the presence of refractory hypertension. Results: The mean age of the patients with refractory hypetension was 68±11 years, 34% were male and they were treated with an avarage of 3.7 antihypertensive drugs. No differences were observed in the distribution of Pro12Ala PPARG and Glu298Asp NOS3 genotypes or alelles between the groups. However, we found that the -786C alelle was more frequent in the group of patients with refractory hypertension (33.3%) than in the group of patients with controlled high blood pressure (17.7%) (p=0.014 OR: 2.32 CI:1.17-4.93). Conclusions: The allele -786C of the NOS3 gene has been previously asociated with a lower activity of the eNOS, our results suggest that this allele may be involved in predisposition to refractory hypertension. The resistance to convencional therapy could be determined at endothelial level. 960-198 Left Ventricle Concentric Remodeling: A First Step of Impaired Cardiac Performance in Middle Aged Subjects With Masked Hypertension Maria V. Papavasileiou, Athanasios Anadiotis, Maria Kokladi, Konstantinos Thomopoulos, Spilios Karas, Sismanoglion General Hospital, Athens, Greece Background: Left ventricle concentric remodeling constitute an earlier step of cardiac hypertensive damage. In this setting, we investigated the degree of left ventricle mass index (LVMI), and relative wall thickness (RWT) in 358 consecutive middle aged subjects divided in hypertensives, white coat hypertensives, masked hypertensives, and normotensives. Methods: we performed twice, a 24h ambulatory blood pressure monitoring (ABPM) in all subjects. According to ABPM, and ofﬁce blood pressure (BP) measurements subjects were divided in: 195 essential hypertensive subjects [group A, M/F=106/89, aged 49±11 years, body mass index (BMI)=28±3 Kg/m2) with ofﬁce systolic/diastolic BP (SBP/DBP)= 158±17/101±8, 24hSBP/DBP=136±12/88±8 mmHg], 75 white coat hypertensives (group B, M/F=27/48 aged 54±13 years, BMI=27±3.7 Kg/m2, SBP/DBP=153±13/96±5, 24hSBP/ DBP=117±6/73±4 mmHg), 19 masked hypertensives (group C, M/F=6/13 aged 44±10 years, BMI=26±3 Kg/m2, SBP/DBP=121±8/80±4, 24hSBP/DBP=134±10/83±3 mmHg), and 69 normotensives (group D, M/F=31/38 aged 46±14 years, BMI=25±4 Kg/m2, SBP/ DBP=121±9/78±5, 24hSBP/DBP=112±9/71±6 mmHg). All subjects underwent a full echocardiographic exam. Results: LVMI values among the groups A/B/C/D were: 109±30/92±30/99±30/89±22 gr/m2. Masked hypertensive subjects did not meet statistical difference when compared relatively to LVMI with the other three groups (p=NS, in all cases). Similarly RWT values among the 4 groups were: 0.44±0.08/0.41±0.08/0.43±0.01/0.38±0.06. Masked hypertensives demonstrated signiﬁcantly higher values of RWT compared to normotensive subjects (p=0.045), and to white coat hypertensives (p=0.04). Multiple regression analysis model performed in the masked hypertensive group has shown that RWT was correlated to BMI (p=0.035). Conclusions: An incremental increase of LVMI and RWT was assessed throughout the four study subpopulations, with masked hypertensive group being a step below hypertensive group. In this setting, middle aged subjects with masked hypertension were found to present left ventricle concentric remodeling, and early treatment may reduce cardiovascular risk in such subjects. ACC_2006_8_VascularDisease.indd 325 1/4/06 5:21:10 PM 326A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n POSTER SESSION 961 Metabolic Syndrome, Obesity and Diabetes Monday, March 13, 2006, 9:00 a.m.-12:30 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 961-199 The Inﬂuence of IIb/IIIa Agents on Mortality in Patients With Risk Factors for the Metabolic Syndrome Undergoing Percutaneous Coronary Revascularization A. Vijay Rathinam, Rapheal Ngengwe, Ryan Zuzek, The Cleveland Clinic Foundation, Cleveland, OH Background: The constellation of hypertension, dyslipidemia, central obesity, and diabetes is the metabolic syndrome (MS). MS has been shown to increase mortality after CABG. In addition, recently it was shown that multiple adverse cardiac events after percutaneous coronary intervention (PCI) were strongly inﬂuenced by the number of risk factors for MS. The inﬂuence of treatment with IIb/IIIa agents on outcomes after PCI has not been studied. Methods: Patients who underwent PCI with use of IIb/IIIa agents and two or more risk factors for MS between January 2000 and November 2002 were identiﬁed. 2006 pts formed the study population. 1046 patients with zero risk factors for MS and use of IIb/IIIa agents during PCI were used as a control group. Patients (1760) with two or more risk factors for MS were grouped together along with the control group and followed prospectively for mortality. Results: The median follow-up was 12 months with 184 total deaths. Mortality difference between patients with risk factors and those without are (7.2% vs. 4.8%) with a p value <0.0001 via chi squared analysis. Conclusion: The presence of two or more risk factors for the MS signiﬁcantly increases mortality in patients undergoing PCI even with concomitant IIb/IIIa use. 961-200 Coronary Disease Prevalence on Stress Imaging in Patients With NCEP Deﬁned Metabolic Syndrome versus Traditional Risk Factors Lindsay Ligler, Masoor Kamalesh, Stephen Sawada, Indiana University Medical Center, Indianapolis, IN Background: Whether metabolic syndrome (MS) is associated with coronary disease risk (CAD) over and above traditional coronary risk factors (CRF) of hypertension, diabetes, smoking and elevated LDL cholesterol is unclear. We investigated the incidence of CAD in a cohort subjects referred for stress imaging studies. Methods: Between 1/04 and 6/05, all patients referred for stress imaging studies for clinically indicated reasons at our hospital were enrolled. A stress myocardial perfusion imaging study was considered positive if it showed ﬁxed or reversible perfusion defects. A stress echocardiographic study was considered positive in the presence of resting or stress- induced wall motion abnormalites. MS was deﬁned according to NCEP-ATP III criteria Results: A total of 1520 consecutive subjects (mean age 62 yrs, 97% men) were enrolled. .The results of stress imaging were correlated with MS and the number of CRF. CAD prevalence was the same in patients with 3 or more CRF and MS alone(p=0.8807). CAD prevalence was lower in patients with < 3 CRF and no MS vs 3 or more CRF (p=0.0224) and MS alone (p=0.0284). Patients with 3 or more CRF + MS and MS alone had a similar prevalence of CAD (p =0.62) Conclusion: 1. MS is a stronger predictor of CAD than 2 CRF 2. MS confers similar risk for CAD as 3 or more CRF 3. Addition of 3 or more CRF to MS does not increase CAD presence. group all no CAD % CAD % All 1520 1082 71 438 29 >3CRF 129 88 68 41 32 MS 476 328 69 148 31 Both 237 159 67 78 33 neither 678 507 75 171 25 961-201 The Impact of Metabolic Syndrome and Diabetes on Long-Term Outcomes Following Percutaneous Coronary Intervention Takatoshi Kasai, Katsumi Miyauchi, Widi Njaman, Kan Kajimoto, Sonomi Maruyama, Naozumi Kubota, Hiroyuki Daida, Juntendo University, Tokyo, Japan Background: The prevalence of metabolic syndrome (MS), regarded as a key risk factor for coronary artery disease, is growing. However, the relationship between MS and long- term prognosis after percutaneous coronary intervention (PCI) remains unknown. Methods: 748 consecutive patients who underwent PCI were studied. Patients were categorized by the presence of MS using the NCEP deﬁnition (for obesity we used a BMI≥25 kg/cm2) and furthermore, patients were divided into 4 groups based on the presence of diabetes (DM). Multivariate Cox proportional-hazards regression, adjusted for age, gender, LDL cholesterol, smoking history, presentation of acute coronary syndrome (ACS), left ventricular ejection fraction, multivessel disease, procedural success was done to examine the risks for composite cardiovascular (CV) events including cardiovascular death, non-fatal ACS and stroke between these groups. Results: There were 358 (48%) patients without both MS and DM, 119 (16%) patients without MS with DM, 92 (13%) patients with MS without DM, 179 (23%) patients with both MS and DM. The mean follow-up was 12 ± 4 years. Overall, there were 180 CV events (24%). Patients with MS without DM had the highest risks for CV events; HR 2.40, 1.51-3.66, P<.0001 and patients with both MS and DM also had higher risks; HR 2.10, 1.45-3.05, P<.0001 comparing to patients without both MS and DM. Conclusions: The presence of MS signiﬁcantly increased the risks of CV events in patients undergoing PCI regardless of the presence of DM. 961-202 Effects of Insulin Dependence in Patients With Type 2 Diabetes Mellitus and Advanced Atherosclerosis, on Inﬂammatory Process, Thrombotic Mechanisms and Endothelial Function Charalambos Antoniades, Dimitris Tousoulis, Kyriakoula Marinou, Kyriakoula Marinou, Costas Toutouzas, Christos Pitsavos, Elli Stefanadi, Stella Brilli, Gerasimos Siasos, George Latsios, Christodoulos Stefanadis, Athens University, Athens, Greece Background: Diabetes mellitus and coronary artery disease (CAD) are both associated with endothelial dysfunction, enhanced inﬂammatory process and increased thrombogeneicity. In the present study we compared the effects of non-insulin dependent (NIDDM) and insulin-dependent (IDDM) diabetes mellitus type 2, on inﬂammatory process, thrombotic mechanisms and endothelial function in patients with underlying CAD. Methods: The population of the study consisted of 66 diabetic patients with CAD (30 patients with IDDM aged 64±2 years old and 36 patients with NIDDM aged 65±1.7 years old). Forearm blood ﬂow was measured using venous occlusion strain-gauge plethysmography. Endothelium dependent dilation (EDD) and endothelium-independent dilation (EID) were expressed as the % change of ﬂow from baseline to the maximum ﬂow during reactive hyperemia or after sublingual nitroglycerin administration respectively. Levels of interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), soluble vascular cell adhesion molecule (sVCAM-1), monocytes chemoattractant protein 1 (MCP-1), von Willebrand factor (vWF), tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) were determined by ELISA. Results: EDD and EID were not signiﬁcantly different between patients with IDDM (51.1±4.8% and 71.3±5.3% respectively) and those with NIDDM (52.8±4.79% and 66.2±6.0% respectively). Plasma levels of vWF, t-PA, PAI-1 and MCP-1 were not signiﬁcantly different between IDDM (114.1±9.1%, 9.7±0.9ng/ml, 2.6±0.3IU/L and 306±24 ng/ml respectively) and NIDDM(135.7±12.6%, 11.5±1.05ng/ml, 3.0±0.26IU/L and 281±20.1ng/ml respectively). However, patients with IDDM had signiﬁcantly higher levels of IL-6, TNF-a and sVCAM-1 (6.9±0.57 pg/ml, 3.87±0.43pg/ml and 596±43.4ng/ ml respectively) compared to patients with NIDDM (4.67±0.5 pg/ml, 2.76±0.28pg/ml and 475±26 ng/ml respectively, p<0.05 for all). Conclusions: Patients with IDDM have signiﬁcantly higher levels of IL-6, TNF-a and sVCAM-1 than patients with NIDDM. These ﬁndings indicate that the insulin dependence may induce inﬂammatory process in type 2 diabetic patients with advanced atherosclerosis. 961-203 Relation of Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-3 to Carotid Intima- media Thickness and Elasticity in Younger Adults: The Bogalusa Heart Study Koichi Ono, Ji-Hua Xu, Shengxu Li, Sathanur R. Srinivasan, Wei Chen, Gerald S. Berenson, Patrick Delafontaine, Tulane University Health Sciences Center, New Orleans, LA Background: Low plasma insulin-like growth factor 1 (IGF-1) levels are associated with an increased risk for atherosclerosis in an elderly population. However, the relationship between carotid wall thickness and elasticity, a surrogate measure of subclinical coronary atherosclerosis, and serum levels of free and total IGF-1 and its binding protein-1 (IGFBP- 1) and -3 (IGFBP-3) in young adults has not been established. Methods: We assessed the association of carotid intima-media thickness (IMT) and arterial elasticity {Peterson’s (Ep) and Young’s elastic modulus (Yem)} with traditional risk factors, IGF-1, IGFBP-1 and IGFBP-3 in 428 black and white young adults (72% white, 39% males, mean age 32yr) in a community-based biracial population. Results: Total IGF-1 and IGFBP-3 levels were signiﬁcantly higher in white than in black subjects (p<0.001); and IGFBP-3 was signiﬁcantly higher in females than males ACC_2006_8_VascularDisease.indd 326 1/4/06 5:21:11 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 327A Vascular D isease, H ypertension, and P revention (P<0.01). In univariate analysis adjusted for age, race and sex, reduced total IGF levels correlated with increased carotid IMT (P=0.05); whereas reduced free IGF-1 correlated with increased Ep levels (P<0.05). In a multiple logistic regression analysis including age, race, sex, blood pressure, adiposity and metabolic variables, total IGF-1 was inversely associated with carotid IMT; IGFBP-3 inversely with Ep and Yem. Conclusions: These results suggest that increased levels of total IGF and of IGFBP-3 are beneﬁcially associated with arterial structure and function in younger adults. IGF-1 measurements, carotid IMT, Peterson’’s elasticity modulus (Ep), and Young’’s (Yem) by race White White Black Black P value P value Male Female Male Female Race Sex N 118 192 50 68 Free IGF-1 (ng/ml) 0.426+- 0.231 0.486+- 0.411 0.395+- 0.389 0.529+- 0.368 <0.05 only in males <0.05 only in blacks Total IGF-1 (ng/ml) 267.7+- 78.0 248.6+- 94.9 200.1+- 86.9 210.9+- 77.8 <0.001 NS IGFBP-1 (mg/L) 36.5+- 49.6 52.1+- 37.8 49.0+- 43.2 39.4+- 40.5 <0.001 only in females <0.001 only in whites IGFBP-3 (mg/L) 4.53+- 0.68 4.65+- 0.72 3.69+- 0.87 4.09+- 0.68 <0.001 <0.01 Carotid IMT (mm) 0.895+- 0.156 0.811+- 0.148 0.881+- 0.174 0.897+- 0.154 <0.001 only in females <0.001 only in whites Ep (kp) 47.1+-11.5 43.6+- 12.2 51.7+- 11.7 48.9+- 13.6 <0.001 <0.01 Yem (kp) 229.4+-67.2 195.7+- 72.2 238.2+- 77.3 201.6+- 68.6 NS <0.001 961-204 Which Is the Best Predictor of Cardiovascular Events: Body Mass Index, Waist-to-hip Ratio, or Waist Circumference? Anne Chris Jonkers, Adriaan A. Voors, Felix Zijlstra, Paul E. de Jong, Hans L. Hillege, Wiek H. van Gilst, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Background: There is no consensus as to whether obesity measurements like waist-to-hip ratio (WHR), and waist circumference (WC) are preferred over the conventional risk marker body mass index (BMI) in predicting cardiovascular events. We therefore compared the prognostic value of these anthropometric measurements on cardiovascular outcome. Methods: BMI, WHR, and WC were measured in 7680 individuals (age 50.1 ± 12.7; 3730 male, 3950 female) who participated in the PREVEND study and were free of coronary heart disease. Adjustment for established cardiovascular risk factors in a Cox proportional hazards model provided hazard ratios (HR) and 95% conﬁdence intervals for each measure in predicting major adverse cardiac events (cardiovascular death, myocardial infarction, ischemic heart disease, percutaneous coronary intervention, coronary bypass surgery). The diagnostic value of each measurement was visualized by Receiver Operating Characteristics (ROC) curves and compared by the area under these curves. Results: A total of 236 events, 29 fatal, occurred in 7680 subjects within the 6,25-year follow-up period. When adjusted for age, sex, systolic blood pressure, smoking, diabetes mellitus, urinary albumin excretion, hypercholesterolemia, and family history of coronary heart disease, BMI (HR 1.04 per kg/m²), WHR (HR 1.03 per unit) and WC (HR 1.02 per cm) were all independent signiﬁcant (p < 0.01) predictors for events. The area under the ROC curves demonstrated higher prognostic value of both WHR (0.73, 0.69-0.76) and WC (0.69, 0.66-0.73) than of BMI (0.62, 0.58-0.65): p < 0.001 for differences between BMI and WHR (X² 32.16) and between BMI and WC (X² 37.80). Conclusions: Although BMI, WHR and WC are all independent predictors of cardiovascular events in a population without prior coronary heart disease, both WHR and WC are more accurate than BMI. These ﬁndings support the use of either WHR or WC for predicting the occurrence of cardiovascular events. 961-205 Risk Scores Combining the Complete Blood Count and Basic Metabolic Proﬁle Are Highly Predictive of Death in Both Independent Training and Test Populations Benjamin D. Horne, Heidi Thomas, Brianna S. Ronnow, Joseph B. Muhlestein, Abdallah F. Kfoury, Dale G. Renlund, Donald L. Lappé, Blair M. Kent, Jeffrey L. Anderson, LDS Hospital, Salt Lake City, UT, University of Utah, Salt Lake City, UT Background: The complete blood count (CBC) and basic metabolic proﬁle (BMP) are common blood tests, some of whose components are cardiovascular risk factors (e.g., glucose) or risk score parameters (e.g., creatinine). A risk score combining all CBC and BMP components has not been evaluated. Methods: Patients (N=15,445) undergoing angiographic assessment of coronary artery disease were entered into the Intermountain Heart Collaborative Study registry (1993- 2004). Baseline CBC (hematocrit, hemoglobin [Hgb], red cell distribution width, mean corpuscular Hgb [MCH], MCH concentration, mean corpuscular volume, red blood cells, platelets, white blood cells) and BMP (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, and calcium) were recorded. Patients were randomly assigned by a Mersenne twister to independent training (N=9,338) and test (N=6,107) groups. Separate risk scores were developed in the training group for 30 day, 1 year, 5 year, and 10 year mortality using the weights for each CBC and BMP variable as determined by multivariable regression models (age- and sex-adjusted). In these analyses, CBC and BMP parameters were categorized either as quartiles or into categories based on standard clinical ranges. Risk scores were applied to the test group for validation of the modeling in an independent population of patients. ROC area under the curve (AUC) evaluated model predictive ability in training and test sets. Results: In the training group, risk scores predicted death at 30 days (model �2=420.7, p<0.0001, AUC=0.81), 1 year (model �2=743.9, p<0.0001, AUC=0.80), 5 years (model �2=670.9, p<0.0001, AUC=0.79), and 10 years (model �2=254.6, p<0.0001, AUC=0.78). The independent test population validated the risk scores with similar AUCs: 0.80, 0.79, 0.78, and 0.76 for 30 days, 1 year, 5 years, and 10 years, respectively. Conclusion: In large training and test populations, risk scores combining statistically weighted CBC and BMP components were highly predictive of death. We propose these scores as important additions to risk prediction that can be easily computed in a clinical laboratory for use in improving patient care at negligible incremental cost. 961-206 Can the Body Fat Composition Measurements Using Dual-Energey X-ray Absorptiometry Predict Coronary Artery Disease in Both Sexes? Hong-Seok Lim, Sung-Gyun Ahn, Seong-ill Woo, Jung-Hyun Choi, Soo-Jin Kang, Byoung-Joo Choi, So-Yeon Choi, Myeong-Ho Yoon, Joon-Han Shin, Seung-Jea Tahk, Ajou University School of Medicine, Suwon, South Korea Background: Body fat distribution especially viseral fat accumulation is closely related to coronary artery disease(CAD) than total body fat itself. The aim of this study was to investigate whether the body fat distribution is more important than the amount of total body fat for CAD in both sex and the difference of the body fat composition between women and men could explain CAD pattern. Methods: We measured total body fat mass and regional body fat composition using dual-energy X-ray absorptiometery (DXA) in 368 patients (188 male) who underwent the coronary angiography due to chest pain. Anthropometric parameters such as body mass index and waist-hip ratio (WHR) and metabolic parameters (including plasma lipid proﬁles, high sensitivity C-reactive protein (hs-CRP) were also measured in enrolled patients. A signiﬁcant CAD was deﬁned as stenosis more than 50% in diameter of any major epicardial coronary artery. Results: In CAD groups of both sexes, Age, WHR, log hs-CRP were higher and hypertension, diabetes were more prevalent. Percentage truncal fat mass to total body fat mass ratio (%FMtrunk/FMtotal) were higher in CAD group than non- CAD group in females. Multiple logistic regression analysis of risk factors revealed %FMtrunk/FMtotal was an independent risk factor for CAD in female subgroup(OR 1.153, P=0.003). Subgroup analysis categorized by percentage total body fat mass (%FM) cut-off point (25% for males, 30% for females) revealed %FMtrunk/FMtotal was an independent risk factor for CAD in males with high %FM(OR 1.166, P=0.029). and in both subgroups of females with high %FM(OR 1.491, P=0.047). and low %FM(OR 1.150, P=0.005). Conclusions: Percentage truncal fat mass to total body fat mass ratio (%FMtrunk/FMtotal) representing central fat distribution is a signiﬁcant risk factor for coronary artery disease in females. In females, even with low percentage total body fat mass, the high truncal fat distribution is an independent risk factor for coronary artery disease and they need active therapeutic interventions and close monitoring to prevent the coronary artery diseases. 961-207 Predictors of Sudden Cardiac Death in a Population With High Prevalences of Obesity and Diabetes: The Strong Heart Study Chirag R. Barbhaiya, Peter M. Okin, Mary J. Roman, Richard R. Fabsitz, Elisa T. Lee, Lyle G. Best, Barbara V. Howard, Richard B. Devereux, Weill Medical College of Cornell University, New York, NY Background: Sudden cardiac death (SCD) accounts for approximately half of all coronary heart disease (CHD) deaths, and is often the ﬁrst and only manifestation of CHD. We examined previously known and potential risk factors for SCD in order to characterize risk factors for SCD in The Strong Heart Study population which differs from previously studied populations in having considerably higher prevalences of diabetes and obesity. Methods: We related clinical and laboratory data in 3,637, and echocardiographic left ventricular measurements in 3,008 participants in the second Strong Heart Study examination to SCD. During a mean follow-up of 6.6 years SCD occured in 60 study participants. Occurrence of SCD was determined by independent physician panel. Results: In univariate Cox models, history of MI or CHF, dialysis, diabetes, microalbuminuria or macroalbuminuria, log urine/creatinine ratio, plasma creatinine (all p<.001), hypertension, increased waist to hip ratio, increased HbA1c, higher fasting glucose, triglycerides, ﬁbrinogen, CRP, lower HDL cholesterol (all p<.05) were all associated with increased incidence of SCD, whereas elevated LDL, hypercholesterolemia, smoking, alcohol consumption and elevated BMI were not. Among echocardiographic variables, reduced LV ejection fraction, LV mass, segmental wall-motion abnormalities, decreased midwall shortening, (all p<.001) and increased E/A ratio (p<.002)were associated with an increased incidence of SCD. The strongest independent predictors of SCD on multivariate analysis were diabetes (HR 2.37, 95% CI 1.10 - 5.11), albuminuria (HR 2.98, 95% CI 1.36 - 6.56), plasma creatinine (HR 1.17, 95% CI 1.01 - 1.35), and reduced ejection fraction (HR 2.04 95% CI 1.09 - 14.3). Conclusions: Diabetes, albuminuria, plasma creatinine and reduced ejection fraction are strong, independent risk factors for SCD in this population with high prevalence of diabetes and obesity. 961-208 Despite Greater Co-Morbidities, Diabetes Does not Increase 60-Day or 1-Year Post Stroke Mortality Masoor Kamalesh, John Shen, William Tierney, Indiana University Medical Center, Indianapolis, IN Background: While diabetes (DM) clearly worsens long term prognosis in cardiovascular disease in the long term, its effect on short term mortality post stroke is debated. We investigated this in a very large veteran stroke cohort Methods: The Patient Treatment File was used to identify all patients discharged from any Veterans hospital between 10/90 and 9/97 with a diagnosis of IS (ICD-9-CM codes 434, 436) listed as primary discharge diagnosis.Demographic, morbidity and mortality data were recorded for each patient. Discharge diagnoses 2 through 10 from the index admission were used to identify co-morbidities and construct the Charlson comorbidity index. ACC_2006_8_VascularDisease.indd 327 1/4/06 5:21:11 PM 328A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n Chi-square tests were used to examine differences between diabetics and non- diabetics, and t-tests were used for continuous variables. Time to death was deﬁned as the number of days between the discharge from the index admission and death. Cox proportional hazard model was used to examine the effects of diabetes on the survival times controlling for age, gender, ethnicity, chronic conditions, co-morbidities, hospital utilization and regions. Results: Of 55,094 stroke patients identiﬁed, 98% were male and 13,925 (25%) had (DM). Mean age was similar between DM and non DM (67.2 vs 67.5, p=NS). Charlson index > 2 was much higher in DM (68.2% vs 47.9%, p<0.001). Hypertension, coronary disease, heart failure and hyperlipidemia were higher in DM (p<0.001) while atrial ﬁbrillatiion was lower (p=0.001). Mortality at 60 days and 1 year was similar in both groups (2.9 vs 2.7%, p=NS, 12.6 vs.13.1, p=NS). Conclusions: Despite greater comorbidity, post acute ischemic stroke mortality at 60 days and 1 year is not different between subjects with and without DM POSTER SESSION 977 Atherosclerosclerosis, Plaque Formation, and Transition to Coronary Syndromes Monday, March 13, 2006, 1:30 p.m.-5:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 1:30 p.m.-2:30 p.m. 977-159 Down-regulation of ζ-chain in CD4+ T-cells and in Natural Killer Cells in Patients With Acute Coronary Syndrome (ACS) Enrico Ammirati, Michela Banﬁ, Domenico Cianﬂone, Andrew Cope, Attilio Maseri, Claudia Monaco, Università Vita-Salute San Raffaele, Milan, Italy, Kennedy Institute of Rheumatology, Imperial College, London, United Kingdom Background: Of the various T-Cell Receptor (TCR) subunits, the �-chain is required for coupling antigen recognition to signal transduction events in T-cells. The �-chain is also expressed in Natural Killer (NK) cells, associated to receptors that mediate cytotoxicity. Down-regulation of the TCR ζ-chain has been reported in infectious and inﬂammatory diseases both in T-cells and NK cells, and is thought to contribute to abnormalities in immune responsiveness related to persistent antigenic and/or cytokine exposure. As growing similarities are emerging between atherosclerosis and chronic inﬂammatory diseases, we assessed whether T-cells and NK cells in patients with ACS exhibit loss of expression of the ζ-chain, and whether ζ-chain downregulation correlates with the presence of systemic inﬂammation, as assessed via IL-6. Methods: We studied 32 patients with ACS, 9 patients with Chronic Stable Angina (CSA) and 18 healthy individuals for CD4+ T-cells and 18 patients with ACS, 5 CSA and 13 controls for the study of NK cells. Peripheral blood lymphocytes and serum were collected on admission, and analysed by 3-color ﬂow cytometry for CD3, CD4, CD16 and TCR �-chain. Data are presented as mean % of CD4+ or NK ζdim /total CD4+ or NK ± SD. We assessed IL-6 levels in the peripheral blood via ELISA. Results: A signiﬁcant down-regulation of TCRζ was observed in peripheral blood CD4+ T-cells in patients with ACS (4.55±3.4) compared to CSA (1.25±0.6 p= .0065) and to controls (1.09±1 p<0.0001). Loss of TCRζ chain expression was also observed in NK cells in patients with ACS (5.02±3.3) compared to CSA (1.52±1 p=0.0279). A signiﬁcant negative correlation was found between level of IL-6 and ζ-chain expression in T-cells (r=0.3591 p=0,037). Conclusions: Enrichment of ζdim CD4 T-cells and ζdim NK cells is present in the peripheral blood of patients with ACS compared to patients with CSA, suggesting immune alteration in patients with ACS. The expansion of these populations may be related to persistent antigenic and/or cytokine exposure, as the correlation between level of IL-6 and expansion of ζdim T-cells indicates. 977-160 T Cell Receptor Signaling and Synapse Formation in T Cells From Patients With Acute Coronary Syndrome Sergey Pryshchep, Viola Vaccarino, Susmita Mallik, Jorg Goronzy, Cornelia Weyand, Lowance Center for Human Immunology, Atlanta, GA, Emory University School of Medicine, Atlanta, GA Background: Macrophages and CD4 T cells inﬁltrate into atherosclerotic plaque and contribute to its destabilization by mediating cellular damage. CD4 T cells from acute coronary syndrome (ACS) patients but not those from healthy controls induce VSMC apoptosis. Apoptosis induction involves formation of an organized immunologic synapse, implicating T cell receptor (TCR) triggering. Mechanisms determining the increased responsiveness of ACS patients’ T cells to form a synapse with VSMC are unknown. Methods: CD4 T cells were isolated from peripheral blood of ACS patients and age/sex- matched controls and stimulated by antigen-presenting cells loaded with superantigen. Recruitment of CD3 and LFA-1 molecules to the immunologic synapse was monitored by confocal microscopy. Receptor-induced reorganization of the cytoskeleton was measured by the accumulation of F-actin. Outcome of TCR ligation and synapse formation was assessed by target cell apoptosis. Results: Real-time confocal microscopy of T cell-target cell interactions showed rapid movement of CD3 and LFA-1 to the contact zone for patients’ and control T cells. However, patients’ T cells recruited notably higher amounts of CD3-TCR complexes to the central region of the synapse within the ﬁrst 4 min of conjugate formation (p= 0.006). These T cells had accumulated more F-actin molecules in the peripheral synapse by 10 min after establishing cell-cell contact (p<0.05). As a consequence, stable synapse architecture was achieved in 63% of patients’ compared to 45% of control T cells (p=0.03). The propensity of patients’ T cells to form stable synapses translated into increased target cell apoptosis (p<0.05). Conclusions: CD4 T cells from ACS patients are functionally abnormal in that they respond to TCR ligation with enhanced recruitment of receptor complexes, faster reorganization of the actin cytoskeleton and sustained stabilization of the synapse. As a biologic consequence, such CD4 T cells are more efﬁcient at killing target cells, including VSMC. Augmented T cell activation, initiated by ampliﬁcation of early membrane-proximal signaling events, may expose patients to VSMC damage, weakening of the ﬁbrous cap and plaque rupture. 977-161 The Effect of Atherosclerotic Plaque and Complement Levels on Microbubble Adherence to the Vascular Wall Thomas R. Porter, Jeane M. Tsutsui, Feng Xie, Tom W. Bargar, University of Nebraska Medical Center, Omaha, NE Background: Serum complement (C3) mediates several inﬂammatory responses in cardiovascular disease, including atherosclerotic plaque progression. Perﬂuorocarbon containing albumin microbubbles (PESDA) bind C3 following intravenous (IV) injection and adhere to sites where endothelial dysfunction (ED) exists. The aim of this study was to determine whether C3 may mediate adherence of PESDA to the dysfunctional endothelium overlying atherosclerotic plaque. Methods: In six apolipoprotein deﬁcient mice (apo E - /-) fed a high cholesterol diet for >6 weeks, IV ﬂuorescent PESDA was administered. In three mice, C3 levels were lowered before PESDA injection by cobra venom factor (CVF) pretreatment. Following PESDA injection, serum C3 levels were measured, and the mice were sacriﬁced for ﬂuorescent microscopy (FM) and scanning electron microscopy (SEM) of the aorta. Results: SEM conﬁrmed the adherence of PESDA microbubbles to atherosclerotic plaque, which was not seen in CVF-pretreated apo E-/- mice (arrows, Figure). FM demonstrated that microbubble adherence to atherosclerotic plaque was over ﬁve times greater in apo E-/- mice who were not pre-treated with CVF (median 172 microbubbles/ﬁeld, range 87 to 312; versus median 3 microbubbles/ﬁeld, range 0 to 92 in CVF pre-treated mice; p <0.001 between groups). Conclusions: PESDA-C3 complexes adhere to dysfunctional endothelium in atherosclerotic plaques. This could be a method of imaging inﬂammatory activity at the plaque surface. 977-162 Local Stress Concentration Around Calciﬁed Apoptotic Macrophages in the Fibrous Cap: A New Hypothesis for the Rupture of Coronary Thin-cap Atheroma Lesions Savvas S. Xanthos, Yuliya Vengrenyuk, Stéphane Carlier, Lane Gilchrist, Peter Ganatos, Frank Kolodgie, Renu Virmani, Sheldon Weinbaum, The City College of CUNY, New York City, NY, Cardiovascular Research Foundation, New York City, NY Background: Mechanisms responsible for the sudden conversion of a rupture-prone plaque to a life threatening atherothrombotic lesion leading to acute coronary syndromes are not fully understood. Paradigms remain: (i) why does a plaque rupture in its mid- portion when ﬁnite element models predict maximum tissue stress at the shoulder? (ii) why at physiological stress (blood pressure) lower than modeled from tissue properties? We investigated the mechanical effects of minute impurities in thin cap ﬁbroatheroma to solve these paradigms. Methods: Looking for minute cellular level calciﬁcations or iron deposits formed in the ﬁbrous cap (e.g. by smooth muscle cell or macrophage apoptosis near the necrotic core or by erythrocyte phagocytosis) we used stains speciﬁc for both calcium (Von Kossa) and iron (Hemosiderin) and reviewed histological sections of thin cap ﬁbroatheroma, some of them ruptured. A 3D confocal microscopy technique was also developed for detecting and verifying the existence of the aforementioned inclusions with the use of ﬂuorescence stains (Alizarin Red S.) speciﬁc to calcium. A theoretical model of a minute spherical inclusion (10 micron in diameter) was ﬁnally developed and solved and further veriﬁed by a FEM calculation. Results: We found multiple cases of calciﬁcations and iron deposits in thincaps. These minute calciﬁcations and iron deposits were, heretofore, ignored because they fell below the sensitivity threshold of intravascular ultrasound (IVUS) or other available in vivo imaging techniques and hence their existence went unrecognized. The theoretical model and Finite Element Method solution revealed that these approximately 10 micron rigid inclusions can intensify the local circumferential stress nearly two fold, to values in excess of the reported critical rupture stress of approximately 600 kPa when the cap thickness is equal to or less than 65 microns. Conclusions: The presence of minute cellular level hard inclusions in thin-cap ﬁbroatheroma lesions can facilitate their rupture. This novel hypothesis might explain remaining paradigms of the triggering events leading to vulnerable plaque rupture. ACC_2006_8_VascularDisease.indd 328 1/4/06 5:21:12 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 329A Vascular D isease, H ypertension, and P revention 977-163 Complex Plaques and Coronary Plaque Progression in Patients With Acute Myocardial Infarction Hiroyuki Ozaki, Kiyoshi Hibi, Hideto Yano, Toshiaki Ebina, Shinichi Sumita, Masami Kosuge, Masahiko Kanna, Kengo Tsukahara, Jun Okuda, Naoki Nozawa, Noriaki Iwahashi, Tatsuya Nakachi, Ikuyoshi Kusama, Yoshio Tahara, Satoshi Umemura, Kazuo Kimura, Yokohama City University Medical Center, Yokohama, Japan, Yokohama City University School of Medicine, Yokohama, Japan Background: Previous studies have reported that 25% to 40% of the patients with acute myocardial infarction (AMI) had multiple complex plaques in association with higher incidence of recurrent ischemic events. Widespread activation of inﬂammation across the coronary vascular bed in patients with acute coronary syndrome regardless of the location of culprit lesions suggested pan-coronary process of atherosclerosis. The aim of this study was to clarify whether most plaques including complex and non-complex plaques in patients with multiple complex plaques progress more rapidly than those in patients with single complex plaque. Methods: A total of 72 patients with AMI who underwent IVUS examination to the culprit artery after percutaneous coronary intervention (PCI) and at 7 month follow up were enrolled. Lesions were considered complex if they had > 50% stenosis and had morphologic features such as thrombus, ulceration, irregularity, and impaired ﬂow. They were divided into 2 groups according to the presence of multiple complex plaques by angiography; group M with multiple complex plaques (n=21) and group NM without multiple complex plaques (n=61). In IVUS analyses, we analyzed intermediate plaques on culprit artery. The target plaque had to be at least 5mm apart from the PCI site, and have <50% of percent diameter stenosis by quantitative coronary angiography(QCA) and >40% of plaque burden by IVUS. Results: By angiography, % diameter stenosis of non-culprit complex plaques as determined by QCA increased during 7 months (59 to 65%, n=0.03), whereas those of non-complex plaques did not change (57 to 56%, p=NS). By IVUS analyses, there was no difference in percent plaque volume change of intermediate plaques between the groups (-3.4% vs -4.7%, p= NS). Conclusions: Complex plaques in patients with multiple complex plaques progressed rapidly regardless of the culprit artery, whereas non-complex plaques and intermediate plaques remained stable, indicating that local complex features as well as pan-coronary inﬂammation may play important roles in the progression of atherosclerosis. 977-164 Coronary Atherosclerosis by Intravascular Ultrasound in Women With Suspected Myocardial Ischemia, but No or Minimal Angiographic Disease: A Report From the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation Study (WISE) Study Matheen A. Khuddus, B Clay Sizemore, C. Noel Bairey Merz, Carl J. Pepine, Susan P. McGorray, Eileen M. Handberg, Karen M. Smith, George Sopko, Barry Sharaf, Steven E. Nissen, Gregory O. von Mering, University of Florida, Gainesville, FL Background: We have previously reported an unexpectedly high cardiac event rate in women with no or minimal angiographic coronary artery disease (CAD). We investigated the prevalence and severity of atherosclerosis using intravascular ultrasound (IVUS) in women undergoing coronary angiography for suspected ischemia. Methods: IVUS of the LAD or circumﬂex artery using an automated pullback device was done in 92 women (mean age 54 yrs) without angiographic stenosis >50%. For each subject we measured vessel volume, atheroma volume, lumen volume, percent atheroma volume (calculated as atheroma volume/vessel volume x 100), percent vessel involved (deﬁned as the number of one millimeter segments with atherosclerosis divided by total pullback length), and atherosclerosis (deﬁned as plaque thickness >0.5mm). Results: Over a sample pullback length (mean 36 ± 16mm), 19 women (21%) had no atherosclerosis. For the remaining 73 women (79%) the mean % atheroma volume was 28 ± 9% and the mean maximum plaque thickness was 0.54 ± 0.22 mm. The mean % vessel involvement by IVUS was 40%. Overall, 34/73 subjects (47%) had a % atheroma volume <30%. The largest mean maximum plaque thickness was only 1.27mm. Traditional risk factors including age, hypertension, diabetes, dyslipidemia, family history, absence of birth control pill use, and presence of hormone replacement therapy use strongly correlated with % atheroma volume (r=0.57, p<0.0001) and % vessel involvement (r=0.44, p<0.0001), with the strongest independent predictor of both being age. Conclusions:.Despite the absence of obstructive angiographic disease, the majority of women with risk factors undergoing coronary angiography for suspected myocardial ischemia have underlying atherosclerosis. While overall atheroma volume is modest, it is relatively diffuse (involving 40% of the study vessel on average) and may be related to the increased incidence of adverse cardiovascular events observed in these women. 977-165 Increased Presence of Pro-Coagulant Apoptotic Bodies in Lipid-Rich and Vulnerable Atheroma: A Vehicle to Propagate Cell Death and Pro-Coagulant Potential? Randolph Hutter, Valentin Fuster, Gerhard Bauriedel, Juan Jose Badimon, Mount Sinai School of Medicine, New York, NY, University of Bonn, Bonn, Germany Background: We have demonstrated inﬂammatory cells selectively undergoing apoptosis in lipid-rich plaque to be a major source for tissue-factor expression and progression of athero-thrombotic disease. During the apoptotic process a high number of apoptotic bodies containing fragmented DNA and tissue-factor is shed into the surrounding tissues. However, there is only limited knowledge on the number and distribution of apoptotic bodies in different plaque components and their effect on neighboring plaque cells in vivo. Methods and Results: We compared the incidence of apoptotic bodies labeling positively for fragmented DNA (TUNEL) and for tissue-factor in lipid-rich and ﬁbrotic plaque components. In addition, we evaluated the speciﬁc location and distribution of apoptotic bodies by transmission electron microscopy in coronary atherectomy specimen derived from culprit lesions in patients with stable versus unstable angina. The density of extra-cellular apoptotic bodies was signiﬁcantly increased per high power ﬁeld in lipid- rich versus ﬁbrotic plaques (58±12 vs. 3±12, P<0.05, for TUNEL-positive and 65±14 vs. 6±2, P<0.05, for tissue-factor-positive apoptotic bodies). Interestingly, apoptotic bodies could also be seen attached to and engulfed by lipid-laden macrophages. Transmission electron microscopy showed extra-cellular, membrane-bound and engulfed apoptotic remnants of variable size and pattern. These apoptotic remnants were consistently increased in specimen from patients with unstable versus stable angina (P<0.01). Of note, macrophages containing a high number of apoptotic bodies in their cytoplasm displayed features of apoptosis as well as necrosis. Conclusions: Lipid-rich and vulnerable atheroma have a higher density of pro-coagulant apoptotic bodies. It appears that the phagocytotic capacity for these structures is exhausted and that phagocytes could become apoptotic or necrotic from possible cyto- toxic effects of apoptotic bodies. Therefore, the accumulation of apoptotic bodies in vulnerable atheroma could propagate cell death and could trigger persistent inﬂammation and spread of pro-coagulant material. 977-166 Proteasome Inhibition: A New Road to Coronary Atherogenesis? Joerg Herrmann, Ardan Saguner, Alejandro Chade, Daniele Versari, Monica Olson, Lilach O. Lerman, Amir Lerman, Mayo Clinic Rochester, Rochester, MN Background: The signiﬁcance of proteasome function in atherogenesis remains undeﬁned. Hence, the current study was designed to assess the effects of chronic proteasome inhibitor treatment in a porcine model of early coronary atherosclerosis. Methods: Female pigs, 3 months of age, were randomized to a normal (N) or high cholesterol diet (2% cholesterol, 15% lard, HC) without or with twice weekly SC injections of the proteasome inhibitor MLN-273 (0.08 mg/kg, N+PSI and HC+PSI) for a period of 12 weeks (n=5 per group). Coronary arteries were then harvested, and vasorelaxation was assessed by organ chamber experiments in response to bradykinin (BK, log-10.5 to -6.5 M) and sodium nitroprusside (SNP, log-9 to -5 M). Intima-media ratio was quantiﬁed by histomorphometry, expression of p47phox by immunoblotting, and vascular superoxide generation by oxidative ﬂuorescence microscopy using dihydroethidium. Proteasome activity of peripheral WBCs was assessed in week 1, serum concentrations of LDL, oxLDL, and endothelin-1 in week 12. Results: A single dose of 0.08 mg/kg of MLN-273 resulted in 68±4 and 40±9% proteasome inhibition within 1 and 24 hours after SC injection, respectively. Results are as listed in the table below. Conclusion: Chronic proteasome inhibition increased oxidative stress, endothelial dysfunction, and structural abnormalities of coronary arteries in a large animal model of early atherosclerosis. These ﬁndings imply a “vasoprotective” role of the proteasome in coronary atherogenesis. values are mean +/- SEM, *p<0.05 vs. other groups, **p<0.05 vs N, #p<0.05 vs. HC N HC N+PSI HC+PSI Serum LDL [mg/dL] 28+/-4 254+/-11** 37+/-7 355+/-12** Serum oxLDL [mg/dL] 12.5+/-1.6 19.1+/-1.9** 11.5+/-0.9 32.6+/-3.2* Serum endothelin-1 [mg/dL] 5.1+/-0.4 7.9+/-0.8** 7.9+/-0.7** 5.7+/-0.4# Vasorelaxation to BK log -6.5 M [%] 90+/-2* 69+/-8 * 57+/-6 48+/-13 Vasorelaxation to SNP log -5 M [%] 56+/-7 66+/-6 69+/-7 59+/-11 Intima-media ratio 0.03+/-0.01 0.07+/0.03 0.09+/-0.03 0.15+/0.04** p47 phox/beta-actin densitometric ratio 0.45+/-0.07* 0.69+/-0.03 0.77+/0.1 0.9+/-0.25 Intima oxidative ﬂuorescence [% area] 0.56±0.54* 8.86+/-0.8 6.0±1.7 7.2±2.0 977-167 Apoptosis Is Increased in Diabetes Atherosclerosis Independent of Plaque Lipid Content Randolph Hutter, K. Raman Purushotaman, Pedro R. Moreno, Carolina Valdiviezo, Valentin Fuster, Juan Jose Badimon, Mount Sinai School of Medicine, New York, NY Background: Our group has demonstrated inﬂammatory cells selectively undergoing apoptosis in lipid-rich plaques to be a major source for tissue-factor expression and progression of atherothrombotic disease (Circulation 2004;109:2001-8). In contrast, ﬁbrotic plaques showed a low apoptosis rate. Atherosclerosis progression is accelerated in diabetes mellitus, and there is only limited knowledge on the effect of diabetes mellitus on plaque cell apoptosis in vivo. Methods and Results: We compared the expression of apoptosis as measured by TUNEL labeling of fragmented DNA and active-caspase-3 detection in serial histological sections of lipid-rich and ﬁbrotic aortic atheroma of diabetic and non-diabetic patients. Both techniques identiﬁed lipid-rich plaques from patients with diabetes with the highest apoptosis rate when compared to lipid-rich plaques from patients without diabetes (26±7 % versus 19±5 %, P<0.05, for TUNEL, and 23±5 % versus 17±4 %, P<0.05, for active-caspase-3). Furthermore, both techniques also identiﬁed ﬁbrotic plaques from patients with diabetes with a higher apoptosis rate when compared to ﬁbrotic plaques from patients without diabetes (9±2 % versus 3±1 %, P<0.05, for TUNEL, and 7±2 % versus 2±1 %, P<0.05, for active-caspase-3). Of note, a signiﬁcant number of additional apoptotic intimal cells in ﬁbrotic and lipid-rich diabetic plaques exhibited a morphology characteristic of neovessels. Conclusions: Plaque cell apoptosis is signiﬁcantly increased in diabetes mellitus independent of lipid content. Apoptotic cell death of immature neovessels in patients with ACC_2006_8_VascularDisease.indd 329 1/4/06 5:21:12 PM 330A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n diabetes mellitus could account for the additional burden of apoptosis. These observations suggest that diabetes mellitus has an independent, pro-apoptotic effect on atherosclerotic plaque cells, possibly accelerating atherosclerosis progression and enhancing plaque vulnerability in diabetic patients. 977-168 Aldose Reductase Inhibitor Improves the Deterioration of Shear Induced Nitric Oxide Production by High Glucose Tomio Umemoto, Masatoshi Kuroki, Takanori Yasu, Hiroto Ueba, Masanobu Kawakami, Muneyasu Saitou, Omiya Medical Center, Jichi Medical School, Saitama, Japan Background: Endothelium-derived nitric oxide(NO) regulates vascular homeostasis. Hyperglycemia induces intracellular polyol pathway activation, which results in the aldose reductase(AR)-linked NADPH consumption and generation of oxidative stress. AR and endothelial NO synthase (eNOS) share NADPH as an obligate cofactor, therefore an intracellular NADPH decrease prevents activity of eNOS. In physiological conditions shear stress activates eNOS and stimulates endothelial NO production. Therefore we examined whether AR inhibitor epalrestat improved shear induced endothelial NO production and/or generation of oxidative stress in high glucose condition. Methods: Human umbilical vein endothelial cells (HUVECs) were incubated in normal(5mM) and high(30mM) glucose for 72 hours, with or without 10, 100nM/L epralrestat, respectively. Then lactate/pyruvate ratio, considered as the reliable indicator of the cytosolic NADH/NAD+ ratio, was measured in each medium. After exchange of medium for Krebs’ buffer HUVECs were exposed to steady laminar ﬂuid shear stress of 12 dyn/cm2 for 5 minutes using the cone-plate viscometer as previously described. NO release from HUVEC was measured using a NOx analyzing HPLC system by Griess reaction. Next cells were harvested in lysis buffer, and phosphorylation of Akt(shear stress induced intracellular signal transduction) and eNOS was analayzed by western blotting. And intracellular 8-OHdG was measured for estimation of oxidative stress. Results: In high glucose condition lactate/pyruvate ratio was higher and shear stress induced NO production was lower compared to normal signiﬁcantly, but 100nM/L epalrestat addition prevented the increase of that ratio and restored NO production(p<0.0 1,respectively). Both high glucose and addition of epalrestat did not affect Akt and eNOS phosphorylation by shear stress. Intracellular 8-OHdG was increased in high glucose condition, but addition of epalrestat signiﬁcantly reduced it dose-dependently. Conclusions: Epalrestat restored shear stress induced endothelial NO production in high glucose condition via inhibition of polyol pathway activity and reduction of intracellular oxidative stress . 977-169 Synergistic Interaction Between Hypercholesterolemia and Diabetes Signaling Through Phosphatidylinositol 3-Kinase/Akt/PKB and Nuclear Factor kB in a Porcine Model of Coronary Atherosclerosis Emile R. Mohler, III, Guanjun Cheng, Damir Hamamdzic, Seyed M. Hashemi, Hashim Osman, Michael S. Parmacek, Morris Birnbaum, Robert L. Wilensky, University of Pennsylvania School of Medicine, Philadelphia, PA Background: The serine/threonine kinase Akt/ PKB is a major regulator of cell growth, proliferation, differentiation, and apoptosis. It is regulated by phosphoinositide 3-kinase (PI3K) via NF-κB transcription factor cascade. It is unknown if AKT activation is pro-atherogenic. Accordingly, we hypothesized that diabetes mellitus (DM) and hypercholesterolemia (HC) had synergistic effects on Akt activation. Methods: Diabetes was induced in male swine by streptozotocin resulting in permanent hyperglycemia. Swine were fed either a normal or HC diet and were randomized into four groups: 1) non-DM, non-HC (control), 2) DM only, 3) HC only, and 4) DM/HC. Coronary arteries were harvested at 6 months. Phospho-Akt, Akt, and IκB-α (inhibitor of NF-κB) protein expression were analyzed using Western blotting Results: Blood glucose averaged from 270-450 mg/dl in DM group, and 50-80 mg/dl in the non-DM group. Blood cholesterol levels ranged from 300-600 mg/dl in HC group and 80-100 mg/dl in non-HC group. In the DM and HC groups Akt activation was not affected whereas in the DM/HC group, there was decreased expression of p-Akt and IκB-α (Figure). Conclusions: This study suggests a potential mechanism by which the synergistic effects of DM and HC affect vascular inﬂammation and coronary atherosclerosis through Akt and NF-kB pathways. 977-170 Modulation of NK Receptors on NK (CD3-/CD56+), T (CD3+/CD56-) and NKT-like (CD3+/CD56+) Cells in Coronary Artery Disease Patricia Aguilar, Georges Clerc, Christine Prin Mathieu, Mohamed Fajraoui, Batric Popovic, Etienne Aliot, Gilbert C. Faure, Marie C. Bene, Gérard Ethevenot, Immunology Laboratory Faculty of Medecine, Vandoeuvre les Nancy, France Background: Atherosclerosis seems to be related with immune dysregulation.Some hypothesis have implicated particularly the role of Natural Killer cells in atherogenesis. Methods: A prospective cohort of 60 patients with coronary disease, 60 controls and 17 patients with a myocardial infarction was studied. The partition of lymphocyte subsets and especially NK (CD3-/CD56+), T (CD3+/CD56-) and NKT-like (CD3+/CD56+) cells was compared in both groups using multiparametric ﬂow cytometry. Moreover, the expression of a series of 7 NK-related receptors (CD161, CD158a, CD158b, CD158e, CD158i, NKG2A and CD244) was compared on the three subsets deﬁned by CD56 and CD3 expression. The NK cell-mediated cytotoxicity against K562 cells was also quantiﬁed with a ﬂow cytometry technique. Results: Comparison between coronary patients and controls showed no signiﬁcant difference between percentages of peripheral NK, T and NKT-cells. Patients with monotroncular lesions (n = 6) had median percentages of NK (CD3-/CD56+) cells more elevated than patients with bi- (n = 53) or tri-troncular (n = 26), lesions, at respectively 18 % versus 11 % versus 8 %, statistically signiﬁcant difference only between mono- and tri-troncular lesions (p = 0.004). NK cells of patients with bi-troncular lesions induced percentages of lysis signiﬁcantly higher than patients with tri-troncular lesions, at respectively 5 % versus 3.5 % (p = 0.03). NK cells’ activity was lower in patients who received statins in comparison with patients without statins, at respectively 6 % versus 17 % (p = 0.05).Patients with a myocardial infarction had a median percentage of NK (CD3-/CD56+) cells signiﬁcantly lower than controls : 8% versus 11 % (p = 0.03) and the percentages of NK- and NKT-cells expressing the receptor NKG2A were signiﬁcantly higher than controls : 48 % versus 41 % and 44 % versus 23 % (p < 0.05). Conclusions: These results showed an increase of peripheral NK cells in patients at onset of atherosclerosis (mono-troncular lesions) in comparison with controls, and lower numbers as well as activity of NK cells in patients with multiple tri-troncular lesions suggesting a NK cells’ migration from peripheral blood to atherosclerotic plaques. 977-171 Effects of Nicotinic Acid on Monocytes: Potential Implications for Atherosclerosis Julia M. Ayala, Sima Patel, Andrew K.P. Taggart, Ester Carballo-Jane, Rebecca Kaplan, Tian-Quan Cai, Julie DeMartino, M. Gerard Waters, Mary Struthers, Merck and Company Incorporated, Rahway, NJ Background: Niacin, or nicotinic acid, has been shown to lower LDL cholesterol and increase HDL cholesterol and improve survival after myocardial infarction. These actions of nicotinic acid are thought to be due, at least in part, to a decrease in lipolysis by adipocytes, mediated through the nicotinic acid receptor, GPR109A. In contrast to the role of this receptor in adipocytes, the presence and function of the GPR109A receptor on primary human immune cells has been considerably less well characterized, despite the fact that the mouse receptor (PUMA-G) was initially cloned from a mouse macrophage cell line. Methods: Using primary human monocytes and in vitro cultured macrophages, we monitored the intracellular calcium release and chemotactic response to nicotinic acid in these cells as well as other downstream effects of signaling through the receptor. Results: In this study we identify a functional nicotinic acid response by primary human monocytes and macrophages. Culturing monocytes with inﬂammatory cytokines known to be upregulated in atherosclerotic lesions enhances the monocyte/macrophage response to nicotinic acid, including calcium ﬂux and chemotaxis. Both responses to nicotinic acid are dose dependent and have similar potency to that observed for GPR109A receptor- dependent responses in previously described biochemical and cell-based systems. We also report a novel effect of nicotinic acid on human monocytes/macrophages: acute treatment with nicotinic acid heterologously desensitizes responses by these cells to the pro-inﬂammatory chemokines, CCL2/MCP-1 and CCL3/MIP-1α. Importantly, CCL2/MCP- 1 is one of the key chemokines implicated in the progression of atherosclerosis. Conclusion: Taken together, these studies indicate that activated monocytes and macrophages reproducibly respond to nicotinic acid and raise the possibility that nicotinic acid may impact atherosclerosis by direct modulation of the behavior and responsiveness of these cells 977-172 In Vivo Real-Time Vessel Imaging and Ex vivo 3D Reconstruction of Atherosclerotic Plaque in Apolipoprotein E-Knockout Mice Using Synchrotron Radiation Microscopy Jin Won Kim, Y. Hwu, Jung Ho Je, Chilh Wan Oh, Byoung Won Cheon, Hyun Hee Kim, Soon Yong Suh, Seung -Woon Rha, Chang Gyu Park, Dong Joo Oh, Hong Seog Seo, Cardiovascular Center, Korea University Guro Hospital, Seoul, South Korea, Pohang University of Science and Technology, Pohang, South Korea Background: We used the unmonochromatized synchrotron x-ray to acquire in vivo real- time and ex vivo images of atherosclerotic lesions in apoE-knockout mice without contrast agents or staining. Methods: In the ﬁve apoE-knockout mice (apoE-/-, 12, 24, 32, 48, 62-week-old, 3 male) and age/sex matched ﬁve wild type mice on cow diets, we acquired in vivo real-time images of thoracic aorta without contrast agents and then, the central arterial trees were dissected intact. In the 32 sites, ex vivo synchrotron images with tomographic reconstruction were done and compared with corresponding pathology.Results: For all living animals, in vivo real-time images of thoracic aorta could be acquired without contrast agents but could not identify the atherosclerotic lesions. Ex vivo images accurately determined aortic wall and atherosclerotic plaque without staining in comparison to histopathology according to the ACC_2006_8_VascularDisease.indd 330 1/4/06 5:21:13 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 331A Vascular D isease, H ypertension, and P revention AHA classiﬁcation (r=0.84, p<0.001, Figure). The volume rendered 3 D images of plaque showed central cholesterol clefts as matched with optical images (Figure). Conclusions: The combination of synchrotron enhanced X-ray microscopy and genetically engineered hyperlipidemic animals would be a useful tool to investigate the changes of advanced atherosclerotic lesions. POSTER SESSION 978 Coronary Artery Remodeling and Function Monday, March 13, 2006, 1:30 p.m.-5:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 1:30 p.m.-2:30 p.m. 978-173 Positive Coronary Artery Remodeling in Women With No or Minimal Angiographic Disease: Intravascular Ultrasound Findings From the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study Matheen A. Khuddus, B. Clay Sizemore, Carl J. Pepine, C. Noel Bairey Merz, George Sopko, Eileen M. Handberg, Susan P. McGorray, Karen M. Smith, Barry L. Sharaf, Steven E. Nissen, Gregory O. von Mering, University of Florida, Gainesville, FL Background: We have previously reported an unexpectedly high cardiac event rate in women with no or minimal angiographic coronary artery disease (CAD). The pattern of coronary remodeling in these women is unknown and may provide insight into the mechanism deﬁning their risk. We investigated the prevalence of positive remodeling by intravascular ultrasound (IVUS) in a sample of these women. Methods: IVUS of the LAD or circumﬂex artery using an automated pullback device was done in 92 women (mean age 54 yrs) without angiographic stenosis >50%. Atherosclerosis was deﬁned as a plaque thickness >0.5mm. Normal reference points were used to determine vessel tapering and to calculate an expected vessel cross- sectional area (CSA) for each 1mm diseased segment. A CSA > 1.05 (expected) deﬁned positive remodeling, a CSA < 0.95 (expected) deﬁned negative remodeling and a CSA 0.95 to 1.05 deﬁned no remodeling. Results: 73 women (79%) had atherosclerosis. In 14 subjects (15%) remodeling could not be classiﬁed because they lacked proper reference segments. Remodeling was assessed in the remaining 59/92 women (64%), for a total of 666 diseased coronary segments. Of these, 73% had evidence for positive remodeling. Conclusions: We found that most women with suspected ischemia and no or minimal angiographic CAD had atherosclerosis identiﬁed by IVUS and positive coronary artery remodeling (Table). Positive remodeling may be linked to the high cardiac event rate previously reported in this population. Prevalence of Coronary Artery Remodeling by IVUS in Women with Atherosclerosis (Deﬁned as Plaque Thickness > 0.5mm by IVUS) Per Patient Analysis (N=59) N (%) No Remodeling (CSA 0.95-1.05) 11 (19%) Positive Remodeling Only (CSA>1.05) 19 (32%) Negative Remodeling Only (CSA<0.95) 5 (8%) Both Positive and Negative Remodeling 24 (41%) Any Positive Remodeling (CSA>1.05) 43 (73%) Per Segment Analysis (N=666) N (%) No Remodeling (CSA .95-1.05) 263 (39%) Positive Remodeling (CSA>1.05) 226 (34%) Negative Remodeling (CSA<0.95) 177 (27%) 978-174 Coronary Remodeling Is the Main Contributor to Lumen Narrowing in Diabetic Patients Pilar Jiménez-Quevedo, Manel Sabaté, Cecilia Corros, Fernando Alfonso, Alfonso Suarez, Rosana Hernández-Antolín, Camino Bañuelos, Esther Bernardo, Celia Ramirez, Dominick J. Angiolillo, Raul Moreno, Javier Escaned, Carlos Macaya, Hospital Clínico San Carlos, Madrid, Spain Background: Plaque progression and negative remodeling are two mechanisms that can produce new coronary stenosis. The aim of this study was to evaluate the main mechanims of new narrowing assessing by IVUS in diabetic patients. Methods: Serial intravascular ultrasound (IVUS) analyses from patients enrolled in the DIABETES (DIABETes and drug Eluting Stent) I and II trials were included in this substudy. Quantitative volumetric analyses were performed from motorized pullbacks (constant speed of 0.5 mm/sec), which were carried out immediately after stent implantation and at 9-month angiographic follow-up. The coronary segment eligible for serial analysis had to be located at least 10 mm distal or proximal from the previously stented segment, and thus, not subject to balloon injury during the index procedure. New narrowing (NN) was deﬁned as a delta lumen value <0. Results: Fifty-six diabetic patients (60 coronary segments) were included in the study. Mean age was 67±9 years, 62% were male and 21% were insulin-dependent. The coronary segment subject for the analysis measured on average 12±3 mm. We found NN in 21 lesions (35%). At follow-up the lesion with NN had negative remodeling (delta vessel area: -2.5±2.7 vs 2.6±2.4, p<0.001), with plaque regression (delta plaque area: -1.0±1.6 vs 1.0±1.4, p<0.001) and signiﬁcant decreased in the lumen dimensions (delta lumen area: -1.5±1.5 vs 1.6±1.4, p<0.001) as compared with non-NN lesions. Conclusions: Negative remodeling appeared to be the main contributor to NN development during follow-up in diabetic patients. 978-175 Is There an Impaired Coronary Collateral Function in Patients With Diabetes Mellitus? Invasive Assessment in Chronic Total Coronary Occlusions Gerald S. Werner, Gero Schwarz, Michael Fritzenwanger, Markus Ferrari, Hans R. Figulla, Medizinische Klinik I, Klinikum Darmstadt, Darmstadt, Germany, Klinik Innere Medizin I, Friedrich-Schiller-University, Jena, Germany Background: The mortality from coronary artery disease is increased with diabetes mellitus. An impaired collateral function is suggested as a possible cause, but the clinical evidence is inconsistent. We used an invasive assessment of collaterals in diabetic and nondiabetic patients with chronic total coronary occlusions (CTOs) as a human in vivo model of collateral development. Methods: In 189 patients with a CTO (>2 weeks duration) coronary blood ﬂow velocity (APVd) and coronary pressure (Pd) were measured distal to the occlusion by sensor wires before the ﬁrst balloon dilatation. From these parameters, aortic (PAo) and central venous presssure (CVP), a collateral resistance index RC=(PAo-Pd)/APVd and a peripheral microvascular resistance index RP=(Pd/APVd) were calculated. The collateral pressure index was calculated as (Pd-CVP)/(PAo-CVP). 65 diabetic patients (34%) were compared to 124 nondiabetic patients. Data are x±SEM. Results: RC was similar in diabetic and nondiabetic patients (RC: 7.6±0.7 vs. 7.0±0.5 mmHg/cm/s). However, the underlying hemodynamic parameters showed differences. Pd was higher in diabetic patients (49±2 mmHg vs. 43±1 mmHg; p=0.002), who also had a higher prevalence of hypertension (88% vs. 75%; p=0.04). The collateral pressure index was higher in diabetic patients (0.41±0.02 vs. 0.36±0.01; p=0.01). In contrast, the APV tended to be lower in diabetic patients (10.4±0.7 cm/s vs. 11.4±0.6 cm/s; p=0.28) with a signiﬁcantly lower contribution during diastole (8.1±0.7 cm/s vs. 10.2±0.6 cm/s; p=0.04) while systolic APV was similar. These differences were more pronounced in patients with a recent occlusion of 2-12 weeks duration. but RP tended to be higher (5.9±0.4 vs. 5.0±0.3 mmHg/cm/s; p=0.12) indicating an impaired microvascular circulation. Conclusions: The collateral function in diabetic patients seem to reach similar levels as in nondiabetics in case of a longstanding CTO. However, there is a markedly reduced diastolic collateral ﬂow in the presence of higher perfusion pressures indicating differences in microvascular properties. There is a larger difference in collateral function in patients with recent CTOs as evidence of a delayed development. 978-176 Intra-Plaque Hemorrhage in Diabetic Atherosclerosis is Characterized by Increased Microvessel Complexity, Intra-luminal Macrophages, and Intra-luminal Red Blood Cells. K-Raman Purushothaman, Valentin Fuster, Marc Sirol, Randolph Hutter, Samin K. Sharma, Pedro R. Moreno, Mount Sinai School of Medicine, New York, NY Background: Intra-plaque hemorrhage (IPH) may be asymptomatic or evolve into high- risk plaques leading to rupture and thrombosis. Patients with diabetes mellitus (DM) are at higher risk for acute events, and differences in IPH may explain in part this degree and intensity of atherosclerotic disease in DM. This study was designed to test the hypothesis that IPH in DM is characterized by increased microvessel complexity, intraluminal macrophages (macs) and intraluminal red blood cells (RBCs) when compared to non- DM plaques. Methods: Five hundred and thirty high power ﬁelds (40x) from 33 lipid rich plaques with IPH (DM=22; Non-DM=11) were randomly evaluated for microvessel complexity. Intraluminal macs, and Intraluminal RBCs were identiﬁed by double immunohistochemistry (CD34, CD3 and CD68). Microvessel complexity was deﬁned as sprouting and branching microvessels with peri-luminal macs, as shown below in Image. Results: DM plaques with IPH had increased mv complexity, intraluminal macs and intraluminal RBCs when compared to non-DM plaques with IPH (see Bar graphs and Image). Conclusion: Diabetic atherosclerosis with IPH is characterized by increased microvessel complexity, and higher counts of intraluminal macs, and intraluminal RBCs, which may explain in part the signiﬁcant degree and intensity of atherosclerotic disease in DM. ACC_2006_8_VascularDisease.indd 331 1/4/06 5:21:13 PM 332A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n 978-177 Effect of Vasa Vasorum Flow on Local Aortic Wall Heat Production in a Rabbit Model: New Insights in the Vulnerable Plaque Konstantinos Toutouzas, Dimitrios Iliopoulos, John Mitropoulos, Maria Drakopoulou, Theodoros Papaioannou, John Karabelas, Eleftherios Tsiamis, Christodoulos Stefanadis, First Department of Cardiology, Athens, Greece Background: Recent studies showed that angiogenesis in the vasa vasorum (VV) destabilize atheromatic plaques, as gives rise to inﬂammation causing plaque vulnerability. Inﬂammatory activation is associated with heat production. We hypothesized that impairment of VV ﬂow would be associated with reduced heat production in rabbit descending thoracic aortic wall (DTAW). Methods: In 10 male anesthetized rabbits left side thoracotomy was performed and baseline temperatures (T) of 2 adjunctive areas of the DTAW were measured by 2 sensitive thermistors (Th); 1 Th for each area. Thereafter the periaortic fat that contains the VV of the DTAW was removed from the ﬁrst area, while the other area was assigned as the control area. Immediately after VV denudation the 2 sensitive Th were stabilized on the DTAW stitches. One Th was stabilized at the denudated region and the other Th at the control area. The leads of the Th were placed subcutaneously. At the end of the procedure T was monitored at both sites and the animals were fed with hypercholesterolemic diet. T measurements were repeated after 1 and 3 weeks. Results: One rabbit died 5 days after the procedure. Baseline T was similar between the 2 groups (38.6±0.3 vs 38.7 ±0.3oC, p=NS). An acute decrease in local T was detected at the region without VV compared to the T of the control site (37.9±0.3 vs 38.7 ±0.4oC, p<0.01). This difference was maintained at one (38.0±0.3 vs 38.9±0.3oC, p<0.01) and at 3 weeks (38.3±0.3 vs 39.1±0.3oC, p<0.01). Conclusions: Interruption of VV ﬂow led to an acute and chronic decrease of heat production in rabbit atheromatic aortas. This experimental study provides new insight in the role of VV in plaque vulnerability. 978-178 C-Reactive Protein May Be Absorbed Through Yellow Plaque and Lead to the Formation of Vulnerable Plaque Shigenobu Inami, Shunta Sakai, Fumiyuki Ishibashi, Kentaro Okamatsu, Beni Ogawa, Daisuke Murakami, Kenichirou Tajika, Kenichi Tokuyama, Kohji Seimiya, Masamiti Takano, Takayoshi Ohba, Norihiko Ohno, Atsunobu Nomura, Satoshi Okumua, Kyoichi Mizuno, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan Background: Deep yellow plaque are observed at the site of culprit lesion in patient with acute coronary syndrome. Recently It was reported that immunohistochemical staining for CRP was increased in culprit lesions of unstable angina, which were obtained by directional coronary atherectomy. However, the origin of focal CRP remains unclear. We investigated whether circulating CRP is absorbed through coronary plaque. Methods: In 19 patients with ischemic heart disease, coronary arteries were explored with coronary angioscopy. One plaque per patient was selected at random. Blood samples from proximal and distal sites of this plaque were collected using the micro- tube catheter and high-sensitivity CRP (hs-CRP) was measured. According to intensity of yellow, plaques were assigned to two groups; 1) deep yellow (group Y, n=7) and 2) light yellow or white plaque (group W, n=12). Results: In group W, proximal and distal levels of the logarithm of hs-CRP(mg/dl) did not differ between proximal and distal of hs-CRP levels(1.09±0.63, 1.10±0.62, respectively: P=0.587). In group Y, distal level of the logarithm of hs-CRP were signiﬁcantly decreased compared with proximal level (0.84±0.51,0.80±0.53, respectively: P=0.007) Conclusions:CRP signiﬁcantly decreases at distal site of deep yellow plaque that is thought to be vulnerable plaque. Our results indicate CRP may be absorbed through yellow plaque and lead to the formation of vulnerable plaque. 978-179 Reversible Impairment of Coronary Blood Flow and Coronary Flow Reserve in Patients With Chronic Atrial Fibrillation George E. Kochiadakis, Michael I. Hamilos, Emmanuel G. Manios, Emmanuel M. Kanoupakis, Hercules E. Mavrakis, Emmanuel I. Skalidis, Nikolaos E. Igoumenidis, Panos E. Vardas, Heraklion University Hospital, Heraklion, Greece Background: In this study we assess for ﬁrst time the effect of chronic atrial ﬁbrillation (CAF) on coronary circulation in humans. Methods: In 12 patients (8 men, mean age 50±12 years) with CAF (>6 months) and normal coronary vessels, baseline and hyperemia blood pressure (BP) and Doppler phasic coronary ﬂow velocity (using a 0.014” intracoronary Doppler ﬂow wire in the proximal LAD) were measured, during AF and 1 hour after elective cardioversion to sinus rhythm (SR). Coronary ﬂow (CF) as the product of total ﬂow velocity integral, heart rate and cross sectional area (CSA) at the site of the Doppler crystal, as well as coronary ﬂow reserve (CFR) as the ratio between hyperemia and baseline values were calculated. Results: The electrical cardioversion of AF to SR was associated with a signiﬁcant decrease in heart rate (from 80±12 to 72±8 bpm, p<0.01), a non-signiﬁcant decrease in mean BP (from 95±12 to 94±12 mmHg) and a signiﬁcant decrease in rate-pressure product (from 7580±911 to 6678±850 beats/min×mmHg, p<0.001). For coronary circulation variables, electrical cardioversion caused a signiﬁcant increase in CSA (from 0.09±0.05 to 0.11±0.04 cm2, p<0.001), a non-signiﬁcant increase in CF (from 95±54 to 97±55 ml/ min) and a signiﬁcant increase in CFR (from 3.27±0.90 to 4.36±0.95, p<0.001). Conclusions: Our ﬁndings suggest that CAF causes vasoconstriction in epicardial coronary arteries and a severe reduction in CFR. This may have deleterious consequences in patients with coronary artery disease. Moreover, the fact that the above measurements improve signiﬁcantly after sinus rhythm restoration, suggests that AF cardioversion may be preferable than heart rate control in patients with chronic AF. POSTER SESSION 979 Peripheral Arterial Intervention Monday, March 13, 2006, 1:30 p.m.-5:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 1:30 p.m.-2:30 p.m. 979-180 Carotid Angioplasty and Stenting under Protection. Short Term Outcomes in High and Low Risk Patients Michel Henry, Isabelle Henry, Antonios Polydorou, Amanda Polydorou, Edmond Le Borgne, Michèle Hugel, Cabinet de Cardiologie, Nancy, France Background: Recent studies have shown that Carotid Angioplasty and Stenting(C.A.S) has superior short term outcomes than Carotid Endarterectomy (CEA) in high surgical risk patients (HR).It is not clear however,whether low surgical risk patients (LR) are also at lower risk.We compared short term outcomes of C.A.S in H.R and L.R patients. Methods: We analyzed all C.A.S performed under protection devices.HR factors included age≥80,post surgical restenosis,prior neck surgery or radiation,contralateral occlusion, low or high anatomic lesion, unstable or severe coronary or hearty diseases,severe comorbidities.Patients were followed for 30 days. Results: 557 CAS were done under protection devices using occlusion balloon(n=334), ﬁlters(n=217), reversal ﬂow technique(n=6).362(65%) were found to be at HR and 195(35%) at LR. HR and LR patients had similar success rate of protection device deployment (99% both) and stent placement(100% both). There was no statistical difference between occlusion balloon and ﬁlters for 30 day death and stroke rate(0.3% vs 1.1, p=n.s)and embolic events (1.4% vs 1.4%).The 30 day outcomes are shown in the table: HIGH RISK n = 362 LOW RISK n = 195 P VALUE T.I.A. 4 (1.1%) 2 (1%) N.S. MINOR STROKE 2 (0.6%) 0 N.S. MAJOR STROKE 1 (0.3%) 0 N.S. RETINAL EMBOLUS 0 2 (1%) N.S. HYPERPERFUSION SYNDROME 2 (0.6%) 1 (0.5%) N.S. DEATH FATAL STROKE NON STROKE DEATH 2 (0.6%) 2 (0.6%) 1 (0.5%) 1 (0.5%) N.S. N.S. N.S. DEATH AND STROKE 5 (1.4%) 1 (0.5%) N.S. EMBOLIC EVENTS 7 (1.9%) 3 (1.6%) N.S. Conclusion: C.A.S under protection is safe with favourable low event rate in HR and LR patients. LR patients have a trend toward lower death and stroke rate after C.A.S compared to C.E.A, but it is not statistically signiﬁcant. C.A.S should be enlarged to L.R patients. 979-181 Comparison of the effects of Nicorandil and Cocktail to Prevent Radial Artery Spasm During Coronary Angiography Seong Hwan Kim, Eung Ju Kim, Min Gyu Kim, Woo Jung Park, Sang Jin Han, Young Jin Choi, Kyoo Rok Han, Dong Jin Oh, Chong Yun Rhim, Hallym University Medical Center, Anyang-si, South Korea Background: Radial artery spasm is one of the most common complications during transradial approach to coronary angiography, causing considerable patient discomfort or sometimes preventing to continue the procedure. This study was designed to evaluate the effects of nicorandil to prevent radial artery spasm during coronary angiography. ACC_2006_8_VascularDisease.indd 332 1/4/06 5:21:14 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 333A Vascular D isease, H ypertension, and P revention Methods: A randomized study to compare 4 mg of nicorandil and a 10 ml of cocktail solution (mixture of normal saline, isosorbide dinitrate, and verapamil) was done in 100 patients. We examined vasospasms of the radial artery that were expressed as stenosis of the vessel diameter after the transradial approach and radial artery patency by pulse oximetry analysis after one month later. Results: The reductions of systolic and diastolic blood pressures (mmHg) after administration of spasmolytic agents were 2.67±19.63/2.91±11.27 for nicorandil group and -5.49±23.63/-2.18±8.61 for cocktail group. There were no signiﬁcant differences in the systolic BP reduction (P = 0.073) but in the diastolic BP reduction there were signiﬁcant differences compared to baseline BP (P = 0.016). Both vasodilator agents showed a signiﬁcant radial artery vasodilation after intra-arterial administration (from 3.05±0.41 mm to 3.38±0.43 mm, P < 0.001 for nicorandil versus from 2.99±0.60 mm to 3.27±0.59 mm P < 0.001 for cocktail). The decrease of the radial artery diameters after transradial approach were as follows (from 3.38±0.43 to 3.10±0.87 mm, P < 0.001 for nicorandil versus from 3.27±0.59 to 2.84±0.82 mm, P = 0.001 for cocktail). There were no signiﬁcant differences between the two groups in the cases of radial artery spasm (45.8% vs 56.0% in nicorandil and cocktail groups, respectively, P = 0.42), but one patient assigned to cocktail group presented total radial artery occlusion after one month follow-up. Conclusions: Nicorandil with vasodilatory effects by a dual mechanism was as effective as cocktail solution at vasodilating radial artery. Besides, nicorandil also showed clinical superiority over a cocktail solution in preventing radial artery spasm and occlusion. 979-182 Long-Term Results of Carotid Stent Implantation Up to 11-Years in Patients With Carotid Stenosis Jennifer Sugita, Solmaz Ghasemzadeh-Asl, Eric Schluessmann, Kasja Rabe, Heike Goedel, Albrecht Roemer, Klaus Lang, Ilona Hofmann, Thomas Middeldorf, Peter Schneider, Ulrich Oetjen, Catherine Thomalske, Horst Sievert, CardioVascular Center Frankfurt, Sankt Katharinen, Frankfurt, Germany, Sankt Katharinen Hospital, Frankfurt, Germany Background: Stent implantation is gaining acceptance as an alternative to endarterectomy in patients with stenoses of the carotid artery and is recommended in surgically high-risk patients. Yet compared to endarterectomy, only limited information is available regarding the long-term outcomes of carotid stenting. Methods: Since 1993 608 high-grade lesions of the internal carotid artery in 552 consecutive patients have been treated by stent implantation. In 524 lesions the procedure was performed with use of embolic protection devices. 611 stents were implanted. Follow- up investigations included a neurological examination after 1 month and thereafter whenever an event occurred. A carotid duplex scan was performed after 1 and 6 months, therafter anually. A questionnaire was sent every year. Patients: The age ranged from 40 - 90 years (71 ± 9 years). 230 lesions (38%) were symptomatic. 26% of the patients were ineligible for carotid endarterectomy (CEA) according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET). 70% were male. 242 patients (40%) had a contralateral stenosis of > 50% and 50 (8%) a contralateral occlusion. 57% of the patients suffered from coronary heart disease, 72% from hypertension, 31% from diabetes, 53% from hyperlipidemia and 40% were previous or current smokers. Mean percentage of lesion was 75 ± 12%, mean length of lesion was 8.1 ± 4.5mm. Results: The procedure was technically successful in 605/608 interventions. 36 patients had one of the following acute or subacute (<30 days) complications: Cerebrovascular death in 4, non-fatal major stroke in 15, minor stroke in 9, symptomatic dissection distal of the stent in 1, asymptomatic occlusion in 2, non-cerebrovascular death in 5 patients. During follow-up (1041 patient years) 6 cerebral deaths, 7 major, 6 minor ipsilateral strokes and 21 re-stenoses occurred. 51 patients died due to non-cerebral causes. Conclusion: Carotid stenting is a safe and effective technique to prevent stroke in patients with a carotid stenosis. Complications occur mostly within 30 days. Neurological events, cerebrovascular mortality and re-stenosis throughout long-term follow-up are rare. 979-183 Durability of Endoluminal Stenting for Obstructive Lesions of the Subclavian Artery: Multicenter Registry in Japan Sunao Nakamura, Kimihiko Kanno, Shinko Soma, Naoyuki Kurita, Mizuki Hirose, Osamu Hirashima, Akihiko Kanazawa, Koji Hozawa, Hitoshi Nakamura, Kazutoshi Yamamoto, Nobuyuki Makishima, Shotaro Nakamura, Jun Koyama, New Tokyo Hospital, Matsudo, Japan Background: Obstructive lesions of the subclavian artery can result in arm claudication, symptoms of subclavian steal. Aim: To evaluate the safety, efﬁcacy and durability of endovascular stenting for treating 325 obstructive lesions of subclavian artery. Methods: We performed 325 cases of endoluminal stenting for 305 patients (207 males, 64±12 years). All procedures were performed with Palmaz stents (210 cases) and Wall stents (115 cases), 220 cases (72.3%) were used transradial approach. Indications for stenting were arm claudication in 175 cases, subclavian steal syndrome in 72 cases and myocardial ischemia secondary to compromised ﬂow through internal mammary grafts in 58 cases. Results: Procedural success (deﬁned as abolition of pressure gradient across the aorta and subclavian artery and a residual diameter stenosis <20% without major complications was achieved in 324 patients (99.7%). Only one patient had a major complication (mediastinum hemorrhage due to subclavian artery rupture). Baseline diameter stenosis was reduced from 89.6% to 14.2±9.0%, mean systolic pressure difference was reduced 46.4±14.8 mmHg to 4.4±2.4 mmHg (p<0.01). There was no cerebral or distal embolization. In 308 of 325 patients (94.8%) we performed, follow-up angiography ranged from 6 months to 8 years (mean, 41 months). Primary angiographic patency at 5 years was 99% (only 2 restenosis: 1.0%). Conclusions: Endoluminal stenting of the subclavian artery is safe and effective with high technical success and these clinical beneﬁts are durable at least 5 years. 979-184 Endovascular Therapy as First Revascularization Procedure in Ischemic Diabetic Foot Gian Battista Danzi, Roberto Ferraresi, Fabiola Sozzi, Guido Pomidossi, Alberto Formentini, Carlo Caravaggi, Ospedale Maggiore Policlinico, Milan, Italy, Ospedale di Abbiategrasso, Milan, Italy Background: ischemic diabetic foot is a consequence of diffuse obstructive vascular disease with the involvement of distal arteries. These conditions are strictly correlated with major amputation in the diabetic population. The aim of our study was to evaluate the role of PTA, as ﬁrst revascularization procedure in the treatment of ischemic diabetic foot. Methods: from January 2000 to December 2004, 336 diabetic patients (222 male, mean age 69 years) with 369 legs affected by foot ischemia (deﬁned as gangrene or ulcer, pedal pulselessness, TcP02 ≤ 40 mm Hg) underwent PTA as ﬁrst revascularization procedure at our Institution. PTA was considered successful in case of complete vessel recanalization (residual stenosis < 50%) with direct ﬂow in at least one vessel of the foot. The major end point of the study was the rate of limb salvage without major amputation at clinical follow-up. Results: 667 diseased arteries were treated: 3% iliac arteries, 42% femoro-popliteal arteries, and 55% infra-popliteal vessels. PTA was successful in 94% of the cases. The mean length of the treated segment was 15.5 cm. Stent implantation was performed in 15% of the lesions. TcP02 level increased from 23±14 to 46±15 after PTA. Site access complications were observed in 4% of the procedures. A clinical follow-up was obtained in 95% of the patients at 24 ± 14.8 months: the rate of limb salvage without major amputation was 88%. Conclusions: PTA is a safe and effective procedure and should be considered the ﬁrst revascularization option for the treatment of ischemic diabetic foot. POSTER SESSION 980 Carotid Disease Treatment Monday, March 13, 2006, 1:30 p.m.-5:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 1:30 p.m.-2:30 p.m. 980-185 Austrian Risk Score for Carotid Stenting: A 3-Year Follow-Up Alexander Niessner, Robert Hofmann, Alexander Kypta, Clemens Steinwender, Klaus Kerschner, Michael Grund, Juergen Kammler, Franz Leisch, Kurt Huber, City Hospital Linz, Linz, Austria, Wilhelminenhospital, Vienna, Austria Background: Apart from age ≥ 80 yrs, little is known about predictors of long-term outcome after carotid stenting. We sought to form a risk score using variables available in routine patient care. Methods: We prospectively enrolled 533 patients (median age: 71 [IQR: 64-77 yrs], 67% male, 36% symptomatic, 45% coronary artery disease, 17% peripheral artery disease [PAD], 11% heart failure [HF]) undergoing successful carotid stenting. Results: A composite endpoint of stroke, myocardial infarction and all-cause mortality was observed in 20.6% of patients during a follow-up of 3 years. Using Cox regression, we selected independent predictive variables from demographic data, cardiovascular risk factors, laboratory parameters, other vascular diseases and lesion-related variables. The ﬁnal model encompassed the dichotomous variables age (> 80 yrs), anemia (Hb < 12 g/dl), inﬂammatory activation (leukocytes > 109/l or ﬁbrinogen > 450 mg/dl), low HDL (< 40mg/dl), PAD, HF and irregular surface of the carotid stenosis. The risk for an adverse event increased gradually with the number of selected risk factors (p for trend = 5x10- 23). C statistic yielded a value of 0.74 for the generated risk score. Patients with ≥ 3 risk factors (23%) had a particularly poor long-term outcome (OR 5.2, 95% CI 3.5-7.7, P = 3x10-16, Fig.). Conclusions: This score formed by 7 easily accessible variables helps to identify high- risk patients after carotid stenting. The long-term outcome was strongly inﬂuenced by comorbidities. ACC_2006_8_VascularDisease.indd 333 1/4/06 5:21:14 PM 334A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n 980-186 Role of the Middle and Anterior Cerebral Arteries Assessment After Internal Carotid Artery Stenting Anna Kablak-Ziembicka, Tadeusz Przewlocki, Piotr Pieniazek, Piotr Musialek, Rafal Motyl, Zbigniew Moczulski, Krzysztof Zmudka, Wieslawa Tracz, Institute of Cardiology, Jagiellonian University, Krakow, Poland Background. Early ﬂow changes in the Willis circle due to carotid stenting (CS) have not been studied widely. Study aimed to assess ﬂow velocities in the cerebral arteries after successful and neurologically complicated CS. Methods. Group I comprised 72 patients with unilateral internal carotid stenosis (ICAS); Group II - 20 patients with bilateral ICAS. Control group included 50 patients without lesions in extra- and intracranial arteries. Transcranial color-coded Doppler ultrasound was performed prior and within 24 hours after CS, with assessment of systolic velocities in ipsilateral to CS site - middle (iMCA), anterior (iACA) and contralateral middle (cMCA), anterior (cACA) cerebral arteries. Results. Collateral ﬂow via anterior communicating artery (ACoA) was found in all Group II patients and 90% in Group I. In 89(96.7%) subjects CS was uncomplicated. After CS, closure of ACoA and velocity increase by 26% in iMCA was noted in Group I, compared to Controls (p<0.001). In Group II, we found iMCA ﬂow increase by 30% (p<0.001), and enlargement of ﬂow via ACoA (p<0.001), resulting in normalization of cMCA velocities (p=0.928). Hyperperfusion syndrome (HS) occurred in 2 (2.2%) patients with bilateral ICAS; TIA - 1 (1.1%) with unilateral ICAS. In HS, MCA velocities were 2.7 and 7.4-fold higher compared to values before CS, and 2-fold higher than in Controls. In TIA patient, ﬂow velocities decreased by 21% in iMCA. Conclusions. Uncomplicated CS, results in increase of iMCA velocity over 25% as compared to values in Controls. MCA velocities in HS were over 2-fold increased as compared to values seen before CS and in Controls. 980-187 Inﬂuence of Pravastatin on Carotid Artery Structure and Function in Dyslipidemic HIV-Infected Patients Under Antiretroviral Therapy Franck Boccara, Tabassome Simon, Karine Lacombe, Ariel Cohen, Brigitte Laloux, Erwan Bozec, Stephanie Durant, Stephane Laurent, Pierre Boutouyrie, Université Paris- Descartes, Faculté de Médecine; INSERM 652, Paris, France Background: Dyslipidemia with accelerated atherosclerosis is an emerging complication in HIV-infected (HIV+) patients treated with antiretroviral therapy (HAART). The effect of statins on carotid atherosclerosis in this population remains unknown. Methods: We investigated the impact of pravastatin therapy (P+) on intima-media thickness of the common carotid artery carotid (IMT-CCA) and stiffness, aortic stiffness (aPWV) and pulse pressure (PP) in HIV+ patients with hypercholesterolemia (LDL-cholesterol ≥ 160 mg/dL) treated with HAART (> 12 months). With a predeﬁned calculation of the sample size, 42 HIV+ patients with P+ (> 12 months) and 42 age, sex and smoking status-matched hypercholesterolemic HIV+ patients without lipid-lowering treatment (P-) were enrolled. IMT-CCA and PP were determined using a non invasive high-deﬁnition echotracking device and applanation tonometry in a central core laboratory blinded to treatment. Results: Both groups were similar for clinical characteristics including cardiovascular risk factors and HIV parameters. Pravastatin (mean posology: 30±10 mg/day, mean duration: 23±8 months) did not inﬂuence carotid artery structure nor function in HIV+P+ compared with HIV+P- [IMT-CCA: 689±131 µm versus 717±148 µm, p=0.36; Cross- sectional distensibility: 31±14 kPa-1.10-3 versus 28±12 kPa-1.10-3, p=0.25; aPWV: 9.6±1.7 m/s versus 10±1.8 m/s, p=0.25, respectively]. Using logistic regression, determinants of IMT-CCA were age and body mass index whereas age, duration of HIV infection, and mean arterial pressure determined aortic stiffness. Conclusions: The use of pravastatin was not associated with a signiﬁcantly lower carotid IMT-CCA in dyslipidemic HIV+ patients. Randomised trials with statins are needed to conﬁrm if HIV-related atherosclerosis is resistant to pravastatin or to all statins. 980-188 Association Between Carotid Intima-Media Thickness and Aortic Arch Plaque Thickness in the Elderly Tatjana Rundek, Elena Tessitore, Robert R. Sciacca, Ralph L. Sacco, Shunichi Homma, Marco R. Di Tullio, Columbia University Medical Center, New York, NY Background: Aortic arch plaques (AP) ≥ 4 mm in thickness are independently associated with ischemic stroke in the elderly. Carotid intima-media thickness (IMT) is a valid marker of subclinical atherosclerosis and may precede plaque formation. The predictive value of increased IMT for AP is not established. Aim of this study was to determine whether carotid IMT is associated with AP in an elderly cohort. Methods: Stroke-free control subjects from the NINDS-funded Aortic Plaque and Risk of Ischemic Stroke (APRIS) Study, a nested case-control study from the population-based Northern Manhattan Study, underwent transesophageal echocardiography and high- resolution B-mode ultrasound of the carotid arteries. Carotid IMT was calculated as a composite (mean) measure that combines the near and the far wall of the internal carotid artery (ICA), bifurcation (BIF), and the common carotid artery (CCA). The total IMT and IMT at the each carotid segment were considered separately. The association between IMT and AP was analyzed by multivariate regression models adjusted for demographics and traditional vascular risk factors (diabetes, hypertension, high cholesterol, cigarette smoking). Positive and negative predictive values of IMT for AP ≥ 4 mm were calculated. Results: Among 138 subjects studied (mean age 66.3 ± 8.5 years; 48% women), AP ≥ 4 mm was present in 35 (24%) subjects. The 75th percentile of the total carotid IMT was 0.80 mm. The 75th percentile of IMT in ICA was 0.66 mm, in BIF 0.95 mm, and in CCA 0.88 mm. Total IMT (p=0.02) and IMT in BIF (p=0.002) were signiﬁcantly associated with AP ≥ 4mm in univariate model, while only IMT in BIF remained signiﬁcant after adjustment for other risk factors (Odds Ratio 24.2, 95% conﬁdence interval 1.9-306). The positive predictive value for AP ≥ 4 mm of IMT in BIF above the 75th percentile (≥ 0.95 mm) was 42%. The negative predictive value for AP ≥ 4 mm of IMT in BIF below the median value (≤ 0.82 mm) was 87%. Conclusions: 1) Increased carotid IMT at the bifurcation is independently associated with AP ≥ 4 mm. 2) A value of carotid IMT at the bifurcation below the median (0.82 mm) excludes the presence of large AP with excellent accuracy. 980-189 ELOCAS Registry - 5-Year Results of Carotid Stenting in High Volume Centers in Patients with Asymptomatic Carotid Stenosis Jennifer Sugita, M. Bosiers, P. Peeters, K. Deloose, J. Verbist, F. Castriota, A. Cremonesi, H. Sievert, CardioVascular Center Frankfurt, Sankt Katharinen, Frankfurt, Germany, AZ St-Blasius, Dendermonde, Belgium Background: Stent implantation is gaining world-wide acceptance as an alternative to surgery in patients with carotid stenoses. However, it is not generally accepted to do it in asymptomatic lesions. We report the acute and long-term results of carotid stenting of asymptomatic stenoses as observed in 4 high-volume centers. Methods: Between 1993 and 2004, 1268 patients with an asymptomatic lesion were selected with intention to treat with stent implantation. In 1009 (80%) lesions the procedure was performed under embolic protection. 1110 (89%) stents were implanted. Conscientious follow-up was done according to the in-hospital stipulations of each center and was entered into a database both retrospectively and prospectively. Patients: The age ranged from 38 - 92 years (71 ± 8 years). 50% of the patients suffered from hypertension, 21% from diabetes, 46% from hyperlipidemia and 24% were previous or current smokers. Results: The procedure was technically successful in 1264/1268 interventions. Within 30 days 12 patients (0.9%) had one of the following acute or subacute (<30 days) complications: Non-fatal major stroke in 4, fatal major stroke in 3 and non-cerebrovascular death in 5 patients. During follow-up (691 patient years) 5 non-fatal major strokes and 3 fatal major strokes occurred. 38 patients died from non-cerebral causes. Conclusion: Carotid stenting is a safe method for preventing stroke in patients with an asymptomatic carotid stenosis. Neurological events during acute and long-term follow-up are rare. POSTER SESSION 981 Statins, Ezetimibe and Torcetrapib: Back to the Future Monday, March 13, 2006, 1:30 p.m.-5:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 1:30 p.m.-2:30 p.m. 981-190 Statins in the Primary Prevention of Cardiovascular Diseases: Meta-analysis of Randomized Controlled Trials Paaladinesh Thavendiranathan, Akshay Bagai, Alan Brookhart, Niteesh K. Choudhry, University of Toronto, Toronto, ON, Canada, Harvard School of Medicine, Boston, MA Background: The role of HMG-CoA reductase inhibitors (statins) in secondary prevention of cardiovascular (CV) events and mortality is well established. However, their role in primary prevention is controversial. We performed a meta-analysis to determine the effect of statins in the primary prevention of CV, non-CV, and mortality outcomes. Methods: We searched MEDLINE, EMBASE, and Cochrane Collaboration databases for trials published between 1966 and April 2005. We included randomized controlled trials with patient (pt) follow up of ≥ 1 year, more than 100 major CV events, at least 100 pts per arm, and ≥ 50% of the population without CV disease. From each trial, demographic data, lipid proﬁle, and, CV, non-CV, mortality, and adverse outcomes were recorded. Risk ratios with 95% conﬁdence intervals (CI) were calculated for each study using a random effects model. Results: Seven trials with 48,465 pts were included. Eighty percent of enrolled pts had no history of coronary artery disease and mean follow up was 4.3 yrs. Change in total, LDL, and HDL cholesterol were -18.8%, -27.4%, and +3.5%, respectively. With statin therapy, the relative risk reduction in major coronary events (nonfatal myocardial infarction (NFMI) or coronary heart disease (CHD) death) was 26.4% (95% CI: 17.0-34.8, p<0.001), in NFMI was 27.4% (95%CI: 13.3-39.1, p<0.0001), in CHD death was 18.3% (95% CI: 5.1- 29.7%; p=0.008), and in CV mortality was 18.4% (95% CI: 1.4-32.5, p=0.035). There was no signiﬁcant change in overall mortality (OR, 0.92; 95% CI, 0.84-1.01; p=0.091), fatal strokes (OR, 1.09; 95% CI, 0.67-1.76; p=0.727), non-fatal strokes (OR, 0.90; 95%CI, 0.73- 1.10; p=0.302), and the incidence of cancers (OR, 1.07; 95% CI, 0.96-1.19; p=0.21). Conclusion: In pts without CV disease, statin therapy does not reduce overall mortality or strokes but does decrease the incidence of major coronary events, NFMI, CHD death, and CV mortality, without increasing the incidence of cancers. Further evaluation is required to assess whether certain sub-populations of primary prevention pts (e.g. those with multiple CV risk factors) may have extended beneﬁts from statin therapy including a reduction in overall mortality or strokes. 981-191 Effect of Atorvastatin on Atheromatic Plaque Temperature and Systemic Inﬂammatory Status in Patients With Coronary Artery Disease Konstantinos Toutouzas, Eleftherios Tsiamis, Maria Drakopoulou, Elli Stefanadis, John Karabelas, Virginia Markou, Manolis Vavuranakis, Harisios Boudoulas, Christodoulos Stefanadis, First Department of Cardiology, Athens, Greece Background: Previous studies have shown that statins have an anti-inﬂammatory effect. The present study was undertaken to deﬁne the effect atorvastatin, on the local and ACC_2006_8_VascularDisease.indd 334 1/4/06 5:21:15 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 335A Vascular D isease, H ypertension, and P revention systemic inﬂammatory process of atherosclerotic plaques in pts with coronary artery disease (CAD). Methods. We included prospectively 254 pts with CAD. Of them 160 pts treated with atorvastatin for >2 months prior to the intervention and 94 pts were not treated with statins. In all pts local temperature of atheromatic plaque was measured by coronary thermography and systemic inﬂammatory status was assessed by serum C-reactive protein (CRP) levels. Temperature difference (DT) was assigned as the difference between the proximal vessel wall temperature from the maximal temperature at the atherosclerotic plaque. Results. Pts treated with atorvastatin had lower DT compared to pts not treated with statins (0.11±0.08°C vs 0.29±0.28°C, p<0.0001). When analysed by type of clinical syndrome pts treated with atorvastatin had less DT compared to untreated pts (0.15±0.09°C vs 0.45±0.29°C p<0.001 in acute coronary syndrome group, 0.08±0.06°C vs 0.13±0.13°C, p=0.0041 in stable angina group). CRP was signiﬁcantly higher in untreated pts compared to those treated (2.09±2.59 vs 1.22±1.94 p=0.03). The lowest quartile of CRP was associated with lower DΤ compared to the highest (p < 0.001), the 2nd quartile (p < 0.001) and the 3rd quartile (p < 0.001) of CRP. Multivariate analysis showed that the clinical syndrome and the treatment of atorvastatin were the predictors of DT. Conclusions. This is the ﬁrst study demonstrating a parallel effect of atorvastatin on systemic and local inﬂammatory process in pts with CAD. 981-192 Effect of Statin Therapy on Renal Function in Hypertensive African Americans Vasilios Papademetriou, Shahe Garabedian, Veterans Affairs Medical Center, Washington, DC, Georgetown University Medical Center, Washington, DC Background: The effect of statin therapy (ST) on renal function is not clearly established. Some data suggest that ST may cause proteinuria and/or worsen renal function, while other studies suggest improvement of renal function. Data in African Americans (AA) is lacking. Methods: We conducted a case controlled study to assess the effect of chronic ST on serum creatinine (SC) in four hundred, hypertensive AA patients with or without baseline renal insufﬁciency. The treatment group consisted of two hundred patients on ST for at least two years (100 pts with SC <1.4mg/dl and 100 pts with SC>1.5mg/dl) and the control group consisted of two hundred patients who were never treated with statins (100 pts with SC <1.4mg/dl and 100 pts with SC>1.5mg/dl). Data was collected at baseline, (time point at which ST was initiated) and at two years of treatment. Patients were required to be on ST therapy throughout the entire study period. Results: The two groups had similar baseline characteristics: age, blood pressure, and medical regimens; but more patients in the treatment group had diabetes, coronary disease, and hyperlipidemia. Changes in SC were as follows: Serum Cr @baseline Serum Cr @2 years P-value Statin Therapy, Serum Cr <1.4 1.2 1.2 NS Statin Therapy, Serum Cr >1.5 1.8 1.6 <.005 No Statin Therapy, Serum Cr <1.4 1.1 1.4 <.005 No Statin Therapy, Serum Cr >1.5 1.6 1.8 <.005 Overall, SC increased by 0.25mg/dl in the control group, and decreased by 0.1mg/dl in the treatement group(p<0.005). Conclusions: In this retrospective case controlled study in four hundred, hypertensive AA patients, we observed that statin therapy was associated with a statistically signiﬁcant beneﬁt in renal function. 981-193 Does More Aggressive Statin Therapy Increase Muscle and Liver Risk? Krista M. Dale, Nickole N. Henyan, Craig I. Coleman, Jeffrey Kluger, C. Michael White, University of Connecticut Schools of Pharmacy and Medicine, Storrs and Farmington, CT, Hartford Hospital, Hartford, CT BACKGROUND: More aggressive statin therapy (MAST) reduces cardiovascular events more than less aggressive statin therapy (LAST) but the impact on the incidence of liver or muscle toxicity is not known. We performed a meta-analysis of randomized controlled trials comparing MAST versus LAST on markers of liver and muscle safety. METHODS: A systematic literature search was conducted through September 2005 to identify randomized, controlled trials of MAST versus LAST evaluating the impact on transaminases (alanine aminotransferase, aspartate aminotransferase) and creatine kinase (CK) for meta-analysis. Subgroup analysis was conducted separately evaluating lipophilic and hydrophilic statins. RESULTS: Eight randomized clinical trials (n=21,765) were included in this meta- analysis. There was an increased incidence of transaminase elevations [odds ratio (OR) 2.70, (95% CI 1.47 to 4.98)] and CK elevations [OR 6.12 (95% CI 1.36 to 27.54)] in patients receiving MAST. Upon subgroup analysis, transaminase elevations occurred with MAST from hydrophilic statins, whereas the incidence of CK elevations occurred with MAST from lipophilic statins. CONCLUSIONS: More aggressive statin therapy results in higher incidences of CK and transaminase elevations. Increases of transaminase may be more problematic with more aggressive hydrophilic statin therapy while CK may be more problematic with more aggressive lipophilic statins. 981-194 Ezetimibe/Simvastatin Versus Atorvastatin for Attainment of Apolipoprotein B and C-Reactive Protein Goals: A VYVA Substudy Christie M. Ballantyne, Nicola Abate, Thomas R. King, Zhong Yuan, Joanne Palmisano, Andrew Tershakovec, Merck & Co., Inc., West Point, PA Background In addition to low-density lipoprotein cholesterol (LDL-C), a growing body of evidence suggests that apolipoprotein B (apo B) and C-reactive protein (CRP) are also predictive of coronary heart disease risk. The purpose of this substudy was to evaluate changes in LDL-C, CRP, and apo B levels in relation to therapy with ezetimibe/simvastatin (EZ/simva) and atorvastatin (atorva). Methods The VYVA (VYtorin Vs Atorvastatin) trial was a randomized, double blind, 6-week study that compared the lipid-modifying efﬁcacy and tolerability of EZ/simva vs. atorva at mg-equivalent statin doses (10, 20, 40, 80 mg) in 1902 patients with hypercholesterolemia. We analyzed the percentage of patients who reached either the dual target of LDL-C <70 mg/dL and CRP <2 mg/L or the dual target of LDL-C <70 mg/dL and apo B <90 mg/dL. Results 1832 patients were included in the CRP analyses (915 in the EZ/simva group, 917 in the atorva group) and 1790 in the apo B analyses (891 EZ/simva, 899 atorva). Distributions of baseline LDL-C, CRP, and apo B levels were similar across treatment groups. The percentages of patients reaching the dual target for LDL-C (<70 mg/dL) and apo B (<90 mg/dL) or the dual target for LDL-C (<70 mg/dL) and CRP (<2 mg/L) are in the Table. Both treatments were well tolerated. Treatment N %[SE] of Patients Attaining Both LDL-C <70 mg/dL and CRP <2 mg/L (Raw Proportions) N %[SE] of Patients Attaining Both LDL-C <70 mg/dL and Apo B <90 mg/dL (Raw Proportions) Atorva 10 mg 231 1.3 [0.74] 227 3.5 [1.22] EZ/Simva 10 mg 226 8.4 [1.85]* 218 11.0 [2.12]** Atorva 20 mg 228 7.0 [1.69] 221 9.5 [1.97] EZ/Simva 20 mg 232 15.5 [2.38]* 227 26.4 [2.93]** Atorva 10 mg 231 1.3 [0.74] 227 3.5 [1.22] EZ/Simva 20 mg 232 15.5 [2.38]** 227 26.4 [2.93]** Atorva 40 mg 228 12.7 [2.21] 225 19.1 [2.62] EZ/Simva 40 mg 234 26.1 [2.87]** 229 38.4 [3.21]** Atorva 80 mg 230 18.3 [2.55] 226 31.9 [3.10] EZ/Simva 80 mg 223 32.7 [3.14]* 217 54.4 [3.38]** All Atorva 917 9.8 [0.98] 899 16.0 [1.22] All EZ/Simva 915 20.7 [1.34]** 891 32.5 [1.57]** *p<0.01, **p<0.001 vs. atorvastatin EZ=Ezetimibe 10 mg All Atorva=Atorvastatin (10, 20, 40, 80 mg) pooled across all doses All EZ/Simva=Ezetimibe/Simvastatin (10/10, 10/20, 10/40, 10/80 mg) pooled across all doses P-values for treatment comparison with same dose of atorvastatin based on the logistic model with terms for treatment, Visit 2 LDL-C stratum, and baseline LDL-C, CRP, and apo B levels. Conclusion A higher percentage of patients treated with EZ/simva, compared with atorva, reached either the dual target of LDL-C <70 mg/dL and CRP <2 mg/dL or the dual target of LDL-C <70 mg/dL and apo B <90 mg/dL at all dose comparisons studied. 981-195 Effects of Torcetrapib and/or Atorvastatin on HDL and LDL Particle Size and Composition: Results From a Phase 2 Trial Tom Thuren, Amy Longcore, Coralie Powell, James Strand, Kathryn Durham, Charles Shear, Pﬁzer Global Research and Development, New London, CT, Pﬁzer Global Research and Development, Ann Arbor, MI Background: Torcetrapib (T) is a novel CETP inhibitor that raises HDL-C, decreases LDL- C, and reduces atherosclerosis in a rabbit model. T 60 mg is in Phase 3 development with atorvastatin (A) 10-80 mg. The effects of T and/or A on lipid subfractions are reported here. Methods: This multi-center, double-blind (T only), dose-ranging, 2-way factorial study randomized 493 subjects with elevated LDL-C without overt cardiovascular disease to T (0, 30, 60, 90 mg) and A (0, 10, 20, 40, 80 mg) for 12 weeks. Results: HDL2-C, HDL3-C, and apolipoprotein (Apo) A-I levels increased dose- dependently with T across A doses. Increases in Apo A-II with T were more modest. Mean changes from baseline to Week 12 in HDL2-C and HDL3-C with T+A ranged from 7.5 to 20.4 mg/dL (79% to 230%) and 7.2 to 15.3 mg/dL (21% to 45%), respectively. ACC_2006_8_VascularDisease.indd 335 1/4/06 5:21:16 PM 336A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n HDL-C particle size increased dose-dependently with regard to T dose but not A dose (mean changes of 0.8 to 1.1 nm with T 90 mg across A doses compared with 0 to 0.2 nm across the dose range of A alone). LDL-C reductions at Week 12 were accompanied by reduced Apo B-100 levels with both T and A alone, with further reductions of -61.1 (-45.1%), -65.8 (-48.7%), and -76.5 mg/dL (-53.7%) with the 30/80, 60/80, and 90/80 mg doses of T+A, respectively. For T alone, increases in cholesterol levels within large LDL particles at Week 12 were accompanied by cholesterol reductions in medium and small LDL particles. Changes from baseline in cholesterol levels within large, medium, and small subclasses after treatment with T+A ranged from -23.4 (60/40 mg) to 12.2 (60/10 mg), from -15.1 (30/20 mg) to -54.7 (90/40 mg), and from -22.7 (60/40 mg) to -69.5 mg/dL (90/80 mg), respectively. Mean LDL particle size increased by up to 1.2 nm with T (90 mg) at Week 12, but with no additional changes with either A alone or T+A. Mean changes in non-HDL-C at Week 12 decreased with T alone (90 mg), A alone (80 mg), and T+A (90/80 mg) by -54.7 mg/dL (-23.1%), -105.2 mg/dL (-47.1%), and -132.9 mg/dL (-61.2%), respectively. Conclusions: T+A raised cholesterol in HDL subfractions, particularly large particles. T+A lowered the number of LDL particles, as well as cholesterol in small LDL. Phase 3 studies are underway to examine anti-atherogenic effects of T+A. POSTER SESSION 982 Target Organ Damage Monday, March 13, 2006, 1:30 p.m.-5:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 1:30 p.m.-2:30 p.m. 982-196 Association Between Low-grade Inﬂammation and Arterial Stiffness in Patients With Essential Hypertension A. Zervoudaki, P. Pietri, G. Vyssoulis, C. Vlachopoulos, A. Deligeorgis, G. Antonakoudis, Th. Gialernios, C. Stefanadis, 1st Cardiology Department of Athens University, Hippokration Hospital, Athens, Greece Background: Arterial stiffness is an independent risk factor for cardiovascular events among hypertensives. Inﬂammation seems to play a major role in the pathogenesis of both arterial stiffness and hypertension. The aim of this study was to examine wheather low grade inﬂammation is associated independently with arterial stiffness in patients with essential hypertension. Methods: We studied 200 patients with uncomplicated, never treated essential hypertension (average age=51 years, 62.5% males). hsCRP, homocysteine and serum amyloid A (SAA) were considered as inﬂammatory markers. Arterial stiffness was evaluated measuring the Augmentation Index (AIx) and the Pulse Wave Velocity between carotid-femoral (PWVf) and carotid-radial (PWVr) arterial sites. Results: A step wise multiple regression analysis was performed using PWVf, PWVr and AIx as dependent variables, and homocysteine, SAA, hsCRP, age, gender, smoking, diabetes, cholesterol, white blood cells (WBC), heart rate and mean blood pressure (MBP) as independent variables respectively. Both PWVf and PWVr were independently correlated with loghsCRP (β=0.52, P=0.02, 95% CI= 0.08-0.96 and β=0.44, P=0.03, 95% CI= 0.039- 0.85 respectively) while no corellation was found with homocysteine and SAA (P=NS). Finally, no correlation was found between AIx and the measured inﬂammatory markers. Conclusions: In hypertensives, PWV, a surrogate marker of arterial stiffness is independently associated with hsCRP. Wheather inﬂammation might act as a modulating factor of arterial stiffness in chronic hypertension, has to be conﬁrmed 982-197 Increased Arterial Stiffness: A Major Determinant of the White-Coat Effect Giovanni de Simone, Giuseppe Schillaci, Marina De Marco, Fabio Angeli, Gian Paolo Reboldi, Paolo Verdecchia, Federico II University, Naples, Italy, R. Silvestrini Hospital, Perugia, Italy Background: Blood pressure (BP) measured in the ofﬁce is usually higher than the average ambulatory BP (ABP), a difference deﬁned white-coat effect (WCE). Whether WCE is a marker of more severe cardiovascular impairment is still controversial. In particular, whether WCE is associated with impairment of conduit arterial system is uncertain. We studied the 2- element Windkessel model of arterial stiffness in relation to WCE in the PIUMA cohort. Methods: We calculated the difference between ofﬁce and average day-time systolic BP (ΔsBP) in 3,169 participants (1,412 women) and split the population in quintiles. Arterial stiffness was evaluated using an adjusted ofﬁce pulse pressure-to-stroke volume ratio (PP/SV), which has been previously shown to predict cardiovascular outcome independent of echocardiographic LV hypertrophy. Results: there was a strong positive association between PP/SV and ΔsBP (r=0.50, p<0.0001). Signiﬁcant linear, positive trends were found between quintiles of ΔsBP and age, proportion of women, plasma glucose and cholesterol (0.01=130 systolic or 80 mmHg diastolic (both: 154 females, 50±14 yrs). PP/SV was signiﬁcantly higher in OH (0.80±0.28) than normotensive (0.64±0.16, p<0.05), whereas it was not signiﬁcantly different from hypertensives (0.86±0.31), even when controlling for confounders. Conclusions: white coat effect is strongly associated with increased arterial stiffness, measured by the pulse pressure-to- stroke volume ratio, based on a 2-element windkessel hydraulic model. 982-198 Subclinical Target Organ Damage in Masked and White- Coat Hypertension Mikio Arita, Yoshikiyo Matsutani, Ikuharu Morioka, Miyoko Utsumi, Sachiko Suzuki, Chigusa Nakamura, Wakayama Medical University, Wakayama, Japan Background: Recent studies have demonstrated that the masked hypertension, with normal blood pressure(BP) in ofﬁce and high BP at home, has a poor prognosis. We studied endothelial dysfunction of kidney, heart and brachial artery in white-coat and masked hypertension. Methods: We studied the brachial-ankle pulse wave velocity (baPWV), urinary microalbumin/creatinine (Ualb/cr), E/A and LVMI by echocardiography and % ﬂow-mediated dilatation(%FMD) in 94 middle-aged subjects (age:52.7 years, BMI:25.7kg/m2 ) untreated with antihypertensives. We classiﬁed them into the 4 subgroups (Normotensin;NT, White Coat Hypertension, Masked Hypertensin, Sustained Hypertension;HT) by using home(135/85 mmHg) and ofﬁce(140/90mmHg) BP levels. Results: Results are summarized in the table. * p<0.05, **p<0.01 vs NT Conclusions: Functional and structural arterial diseases and endothelial dysfunctions are advanced in asymptomatic patients with masked hypertension. NT White Coat Masked HT n 43 14 13 12 UAlb/UCr (µg/ml/Cr) 9.5±7.8 16.0±6.8* 17.0±5.5* 35.1±7.3** baPWV(cm/s) 1347.6±173.5 1371.7±158.6 1395.6±151.5 1642.2± 293.7** E/A 1.29±0.70 1.19±0.29 1.04±0.29* 1.04±0.30* LVMI(g/m2) 82.2±22.0 90.8±18.3 101.1±21.2** 101.3±26.7** %FMD(%) 16.5±8.3 16.4±5.7 16.4±5.5 12.4±8.0* 982-199 Obesity is Independently Associated With Increased Ventricular Systolic Tension: A Population-Based Study Julio A. Chirinos, Joseﬁna Medina-Lezama, Oscar O. Morey-Vargas, Humberto Zea- Diaz, Juan F. Bolanos, Edgar Munoz Atahualpa, Paola Villalobos, Shirley Paredes, Blanca Zevallos-Buscalla, Mauricio Postigo Mac Dowal, Julio Chirinos-Pacheco, Santa Maria Catholic University School of Medicine, Arequipa, Peru Background: A paradoxical beneﬁtial association of obesity with decreased wave reﬂection, an important determinant of left ventricular systolic load, has been reported. However, obesity imposes an increased risk of heart failure after correction for other risk factors. The mechanisms of this association are unclear. In this study, we aimed to assess the relation between obesity and left ventricular systolic load. Methods: We studied 612 non-hypertensive subjects (346 women and 266 males) as part of an ongoing population-based study. Radial applanation tonometry was performed and central aortic waveforms were obtained with a validated transfer function. The tension-time index (TTI), an indicator of systolic load, was calculated as the pressure- time integral (area under the aortic pressure curve) in systole. The augmentation index (AIx), a marker of the relative amplitude of the reﬂected wave, was deﬁned as augmented pressure (second minus ﬁrst systolic peak) expressed as a proportion of pulse pressure. All reported estimates (β) correspond to one standard deviation increase in BMI. Results: BMI correlated positively with TTI (r=0.30; p<0.0001). The abdominal sagital diameter predicted TTI independently of BMI, indicating that central obesity is a determinant of TTI (p<0.0001). After adjusting for age, gender, heart rate, mean and pulse pressure, increasing BMI predicted a higher TTI (β=355; p<0.0001). In adjusted analyses, increasing BMI also predicted a lower AIx (β=-22; p<0.0001), a longer systolic ejection time (β=37.9; p=0.002), a lower end-systolic pressure (β=-4.1; p=0.001), and a lower mean pressure during diastole (β=-1.9; p=0.001). Conclusions: Despite its paradoxically beneﬁtial effects on the amplitude of the reﬂected wave, obesity is associated with greater left ventricular systolic tension. Obesity is also associated with an increased systolic ejection time resulting in a larger overlap between the primary and the reﬂected wave. The increase in systolic ejection time is associated with a lower end-systolic pressure and a resultant lower mean aortic pressure during diastole. This mechanism may be implicated in the association between obesity and heart failure. 982-200 C-Reactive Protein Levels Is the Major Determinant of microalbuminuria in Essential Hypertensive Patients Chih-Chan Lin, Wei-Chuan Tsai, Yao-Yi Huang, Wei-Ting Li, Cheng-Han Lee, Ju-Yi Chen, Jyh-Hong Chen, National Cheng Kung University Hospital, Tainan, Taiwan,ROC Background:Hypertension is a major risk factor for cardiovascular disease and microalbuminuria is known as an important prognostic factor in hypertension patients. We investigated what is the determinant of microalbuminuria in non-diabetic essential hypertensive patients. Methods: We recruited 157 (age 42 ± 7 years, 107 men) uncomplicated essential hypertensive patients in this study. Exclusion criteria included diabetes mellitus, atherosclerotic cardiovascular disease and augmented serum creatinine concentration (Cr.≥ 1.5 mg/dl). Moreover, we limited the study group to patients who had a body mass index (BMI) < 35 kg/m2. Medical history, body height, body weight, and blood pressure were obtained in each subject. The albumin level (mg) was measured in each 24-hours urine collection. High-sensitive CRP (hs-CRP), blood sugar, insulin, and lipid proﬁles were measured. HOMA index (HOMA-I) was calculated from blood sugar and insulin as an index for insulin resistance. Results: Microalbuminuria was correlated with glucose level (r = 0.222, P = 0.005), and ACC_2006_8_VascularDisease.indd 336 1/4/06 5:21:16 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 337A Vascular D isease, H ypertension, and P revention hs-CRP levels (r = 0.708, P < 0.001) signiﬁcantly. Age, sex, BMI, smoking, lipid proﬁle, and antihypertensive medications did not affect microalbuminuria. After multivariate analysis, only hs-CRP (r = 0.699, p < 0.001) was independently correlated with microalbuminuria. Moreover, hs-CRP levels were signiﬁcantly correlated with body mass index (r = 0.421, p <0.001), high-density lipoprotein (r = -0.299, p <0.001), insulin (r = 0.379, p <0.001), HOMA-I (r = 0.356, p <0.001), mean blood pressure (r = 0.203, p = 0.011), and triglyceride (r = 0.286, p <0.001). Age, sex, smoking, cholesterol, low-density lipoprotein, serum glucose, and antihypertensive medications did not affect hs-CRP. After multivariate analysis, only body mass index (r = 0.241, p = 0.010) was independently correlated with hs-CRP. Conclusions: Hs-CRP is the major determinant of microalbuminuria in uncomplicated essential hypertensive patients. It suggested that urine albumin loss is the consequence of generalized inﬂammatory vascular damage in the kidney. BMI is the major determinant for hs-CRP in these patients.. 982-201 Left Ventricle Diastolic Dysfunction, and Aortic Stiffening in Hypertension: The Web of Causative Interrelationships of Atrial Fibrillation Ioannis Skiadas, Costas Tsiouﬁs, Efstathios Taxiarchou, Apostolis Kakkavas, Pavlos Stougiannos, Christos Katsaris, Pavlos Toutouzas, Christodoulos Stefanadis, Ioannis Kallikazaros, Hippokration Hospital, Athens, Greece Background: Although the sequels of essential hypertension on rhythm disturbances is currently under vigorous investigation, the structural and functional characteristics of the hypertensive heart with paroxysmal atrial ﬁbrillation (PAF), and their prognostic role has not been fully studied yet. Methods: We studied 46 consecutive essential hypertensive subjects (aged 64 years, 22 men, ofﬁce blood pressure (BP) 144/86mmHg) with a history of paroxysmal atrial ﬁbrillation, and no other evident comorbidity and 49 consecutive essential hypertensives without any evidence of PAF, matched for age, sex and BP. All included subjects were on sinus rhythm, and underwent a complete conventional, and tissue doppler imaging (TDI) echocardiographic study. Left Ventricular (LV) diastolic function was estimated by TDI, averaging the diastolic mitral annular velocities measurements. Aortic stiffness was evaluated, on the basis of carotid - femoral pulse wave velocity (PWV) measurements by means of a computerized method (Complior SP). Results: Hypertensives with PAF compared to those without PAF had increased body mass index (28.1vs 26.9kg/m2, p<0.05), were smokers in a higher percentage (45 vs 31%, p<0.05), had a longer duration of hypertension (5 vs 2 years, p< 0.05), showed signiﬁcantly increased relative wall thickness (0.46 vs 0.44, p<0.05), left atrial volume indexed for body surface area (LAV index) (23.7±7 vs 19.7±3 ml/m2 p<0.05), and lower Em (7.5±1.6 vs 8.4±1.4cm, p<0.05), and Em/Am values (0.8±0.1 vs 0.9±0.4 p<0.05). Hypertensive subjects with PAF compared to those without PAF had increased PWV (9.65 vs 8.44 m/sec, p<0.05), and it was positively correlated with age (r=0.54, p<0.001), ofﬁce systolic BP (r=0.35, p<0.05), relative wall thickness (r=0.32, p<0.005), and LA volume index (r=0.29, p<0.05). Conclusions: Hypertensive subjects with PAF have signiﬁcantly higher LAV index, augmented values of aortic PWV, and worse TDI-detected LV diastolic dysfunction. Although the underlying pathophysiological mechanisms are largely undetermined, this association could at least partially explain the increased vulnerability of such patients for development of PAF. 982-202 Relation of Components of the Metabolic Syndrome to Left Ventricular Mass Teimuraz Apridonidze, Hussain Shaqra, Nessrine Ktaich, Eliot N. Heller, Jonathan N. Bella, Bronx-Lebanon Hospital Center, Bronx, NY, Albert Einstein College of Medicine, Bronx, NY Background: Left ventricular (LV) hypertrophy is an independent predictor of increased cardiovascular morbidity and mortality. It remains unclear whether the metabolic syndrome (MBS) are associated with LV hypertrophy. Methods: Accordingly, we analyzed echocardiograms in 192 consecutive ambulatory patients referred for echocardiography from October to December 2004. Patients were excluded if they had atrial ﬁbrillation, signiﬁcant valvular heart disease or failed to cooperate for echocardiogram. Results: 126 (66%) patients met ATP III criteria for MBS. Compared to patients without MBS, MBS patients had similar age (61 years [58.4-63.8 95%CI] vs 60 [55.9-63.2 95%CI] years, p=NS) and were likely to be female than male 46 (64 vs. 37%, p=0.03). MBS patients had higher body mass index (31 kg/m2 [30.1-33.4 95%CI] vs 25 kg/m2 [22.8-27.4 95%CI]), and by deﬁnition had higher prevalence of hypertension (74 vs.26%), diabetes (81 vs. 19%) or hypercholesterolemia (88 vs. 12%, all p < 0.0001). 29% had any 3 MBS components, 18% had any 4 MBS components and 17% had all 5 MBS components. In analyses of variance adjusted for age and sex, LV mass and LV mass adjusted to its allometric relation to height2.7 (LV mass/height2.7) were higher in patients with MBS compared to those without MBS (237 g [228-239 95%CI] vs. 224 g [206-239 95%CI] p=0.005 and 62 g/m2.7 [59-65 95%CI] vs. 56 g/m2.7 [52-60 95%CI] p=0.014, respectively). The prevalence of LV hypertrophy, using prognostically-validated gender-speciﬁc partition values for LV mass/ height2.7 was statistically signiﬁcantly higher in MBS patients than in those without MBS (81 vs. 58%, p<0.001). There was a step-wise increase in LV mass/ height2.7 from 41 g/m2.7 [18-64 95%CI] in those with no MBS components to 55 g/m2.7 [50- 62 95%CI] in those with 1 MBS component to 61 g/m2.7 [56-66 95% CI] in those with 3 or more MBS components (p<0.001). Conclusions: MBS is associated with higher LV mass and prevalence of LV hypertrophy in an ambulatory clinical cohort. Increasing number of MBS components is associated with step-wise increases in LV mass. Identiﬁcation of LV hypertrophy in MBS patients may provide an additional prognostic tool to further risk-stratify these patients. POSTER SESSION 983 Laboratory Enhancement of Risk Prediction Monday, March 13, 2006, 1:30 p.m.-5:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 1:30 p.m.-2:30 p.m. 983-203 A Calculated Glomerular Filtration Rate or a Simple Serum Creatinine: Which is the Better Predictor of Mortality in Patients with Coronary Artery Disease? Heidi Thomas, Tami L. Bair, Jeffrey L. Anderson, Dale G. Renlund, Abdallah G. Kfoury, Benjamin D. Horne, Joseph B. Muhlestein, LDS Hospital, Salt Lake City, UT, University of Utah, Salt Lake City, UT Background: The presence of renal insufﬁciency (RI) indicates a poor prognosis for patients (pts) with coronary artery disease (CAD). Historically, RI has been ascertained from creatinine (CR). More recently, a calculated glomerular ﬁltration rate (GFR) that takes into account CR, weight, age, and gender, has been proposed to be more reﬂective of actual renal function, and therefore, more predictive of clinical outcomes. However, whether this adjustment actually enhances the risk predictive power of GFR over CR in CAD pts is not known. Methods: CAD pts enrolled between 1993-2004, with a CR and long-term follow up for death (D) were studied (N=21,494). Independent and combined CR and GFR models were developed using multivariate Cox regressions adjusting for standard risk factors. GFR was calcuated using the MDRD equation and categorized into 5 groups by ml/min: GFR(1): >90, GFR(2): 60-89, GFR(3): 30-59, GFR(4): 15-29, GFR(5): <15. CR was categorized in mg/dL: CR(1): <1.1, CR(2): 1.1-1.29, CR(3): 1.3-1.49, CR(4): >1.5. Results: Mean age was 62 (±13 yrs); 62% were male; average follow-up was 3.3±2.6 yrs. There were 3,890 (17.7%) D. Multivariate GFR D hazard ratios (HR) vs. GFR(1) were: GFR(2): HR=1.10, p=0.04; GFR(3): HR=1.88, p<0.001; GFR(4): HR=3.78, p<0.001; GFR(5): HR=4.85, p<0.001. Multivariate CR HR vs. CR(1) were: CR(2): HR=1.10, p=0.03; CR(3): HR=1.43, p<0.001; CR(4): HR=2.44, p<0.001. In a multivariate model that included both CR and GFR, GFR better stratiﬁed risk than CR: GFR(2): HR=0.97, p=0.57; GFR(3): HR=1.01, p=0.49; GFR(4): HR=1.97, p<0.001; GFR(5): HR = 2.54, p<0.001 and CR(2): HR=1.10, p=0.15; CR(3): HR=1.40, p<0.001; CR(4): HR=1.90, p<0.001. However, in a subanalysis of women, CR (HR[CR(4) vs. CR(1)] = 2.68 [p<0.001]) was a better predictor of D than GFR (HR[GFR(5) vs. GFR(1)] = 2.00 [p=0.001]). CR also predicted D better than GFR in pts >65 (CR(4): HR=2.03, �2=27.34, p<0.001; GFR(5): �2=12.75, HR=1.99, p<0.001). Conclusion: In CAD pts, GFR was a better predictor of D than CR, but in certain subpopulations (women and >65 years), CR was superior. This brings into question the value of adjusting for age and gender when calculating GFR in these important and prevalent subsets of CAD pts. 983-204 Coronary Calciﬁcation and Left Atrial Size Are of Additive Incremental Value to the Framingham Risk Score for the Prediction of Cardiovascular Events Martin Osranek, Christina M. Wood, Philip R. Araoz, Kent R. Bailey, Teresa S. Tsang, James B. Seward, Thomas Behrenbeck, Mayo Clinic, Rochester, MN Background Coronary calciﬁcation (CC) and left atrial (LA) size are independent predictors of cardiovascular (CV) events. It is unclear if they provide additive information to each other and to conventional cardiac risk assessment by the Framingham score (FS). Methods Individuals who had both CC and LA assessment within 90 days were included in this study. CC was obtained by electron beam computed tomography and quantiﬁed by the Agatston method. LA size was measured by M-mode echocardiography in the anterioposterior dimension. Cardiac death was ascertained by the Accurint® tracking system and review of death certiﬁcates. CV events (MI, stroke) were assessed by medical record review. FS was calculated using gender, age, DM, smoking history, LDL- cholesterol and blood pressure measurements. Results A CV event occurred in 42 of 489 (8.6%) individuals (mean age 56±12 years; 35% women; median FU of 5.5 years): 34 cardiac deaths, 7 MI, and 6 strokes. In a multivariable Cox model, ln[CC] (HR=1.48; p<0.00001) and LA size (HR=1.20; p<0.00001) were predictors of CV events, FS approached signiﬁcance (HR=1.08; p=0.06). Adjusted for FS, the risk for any CV event increased across groups of CC as well as quartiles of LA size (see Figure). Conclusion 1) Quantiﬁcation of coronary calciﬁcation and left atrial size contributed independently to conventional risk assessment (FS) in the prediction of hard CV events. 2) Coronary calciﬁcation and left atrial size were additive to each other in identifying high risk patients. ACC_2006_8_VascularDisease.indd 337 1/4/06 5:21:17 PM 338A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n 983-205 Socioeconomic Status, Inﬂammatory and Hemostatic Markers and Cardiovascular Events Michelle A. Albert, Robert J. Glynn, Julie Buring, Paul M. Ridker, Brigham and Women’s Hospital, Boston, MA, Harvard Medical School, Boston, MA Lower socioeconomic status (SES) is associated with greater cardiovascular risk than higher SES. The mechanism through which SES impacts cardiovascular disease (CVD) is unclear. Data that examine the association between novel CVD risk factors, SES and CVD events are sparse. Methods and Results: We assessed the relationship between two indicators of SES (education and income), traditional and novel CVD risk factors [CRP, s-intercellular adhesion molecule -1 (ICAM), ﬁbrinogen and homocysteine] and CVD events (MI, stroke, coronary revascularization, CVD death) among 22, 688 apparently healthy women over 10 years of follow-up. Median baseline CRP, ICAM, ﬁbrinogen and homocysteine levels for women in 5 categories of education [< 2 years of nursing, 2- 3 years of nursing, Bachelors , Masters and a Doctoral degrees] and 6 categories of annual income [<$19,999 , $20,000 - 29,999, $30,000 - 39,999, $40,000 - 49,999, $50,000 - 99,999 and >$ 100, 000] decreased with increasing education/income (p trend <0.001). In age-adjusted models, the RR of CVD events decreased with increasing education (1.0, 0.7, 0.5, 0.4, 0.5, p trend < 0.001) and income (1.0, 1.0, 0.9, 0.7, 0.6, 0.4, p trend < 0.001). Multivariate analyses of CVD risk adjusted for age, smoking , diabetes, hormone use, hypertension, alcohol, exercise, body mass index, family history of MI, CRP, ICAM, ﬁbrinogen and homocysteine. In models that assessed the impact of traditional and novel CVD risk factors on the relationship between education/income and CVD events, the relative hazard of incident CVD associated with a 1-category higher level of education changed from 0.79 in age-adjusted to 0.89 in fully adjusted analyses. The 11% lower risk per 1 category of education remained signiﬁcant (p trend =0.006), suggesting that control for both novel and traditional risk factors could not explain the protective effect of education. A similar analysis for income revealed that its relationship with CVD events was explained by these noted risk factors. Conclusion: In this prospective analysis, we observed a decrease in CVD events with increasing categories of education, a relationship that is only partially explained by traditional and novel risk factors for CVD. 983-206 A Coronary Artery Calciﬁcation Score ≥ 400 Is Signiﬁcantly Associated With Myocardial Ischemia Independently of Framingham Risk Score John S. Ho, Shannon J. FitzGerald, Susan M. Devers, Michael J. LaMonte, John J. Pippin, Nina B. Radford, Cooper Clinic, Dallas, TX, Cooper Institute, Dallas, TX Background: Multiple risk factor models, such as the Framingham Risk score (FRS), coronary artery calcium (CAC) scores, and myocardial perfusion imaging are noninvasive methods of quantifying coronary event risk in individuals without previously manifest coronary heart disease. However, the interrelationships among these risk predictors are less understood. Therefore, we examined the association of CAC score, independent of FRS, with the presence of inducible myocardial ischemia, a well-established surrogate for future adverse cardiac events. Methods: Participants were 621 men and women (mean ± SD, age 57 ± 9 years) who had myocardial perfusion imaging and CAC scoring with electron beam tomography within 180 days of each other between 1998 and 2004. Inducible myocardial ischemia was deﬁned as the presence of reversible perfusion defects. CAC scores were quantiﬁed using the Agatston method. FRS was based on measured clinical data and was categorized as low (<10%) and moderate-high (≥ 10%) risk. Results: Among the study population, 63 individuals (10.1%) demonstrated inducible ischemia. Univariate predictors of myocardial ischemia were male gender (p<0.001), age (p=0.04), hypertension (p=0.002), diabetes (p=0.005), FRS (p<0.001), and CAC score (p<0.001). A positive dose-response gradient was seen between myocardial ischemia and CAC scores. Inducible ischemia was observed in 5.9%, 11.6% and 22.2% of individuals with CAC scores of < 400, 400-999, and ≥ 1000 respectively (p <0.001 for trend). Logistic regression analysis showed that after adjusting for differences in FRS, the relative odds of inducible ischemia were 2.8 (95% CI, 1.6-4.9) in individuals with CAC scores ≥ 400 compared to those with CAC scores < 400. The relation between CAC score and myocardial ischemia was attenuated but remained signiﬁcant after further adjustment for body mass index and family history of coronary heart disease. Conclusions: CAC scores ≥ 400 are signiﬁcantly associated with inducible myocardial ischemia, independent of FRS. Thus, the CAC score may serve as an important clinical tool in deciding which patients require functional testing to assess the presence of obstructive coronary disease. 983-207 Subclinical Coronary Atherosclerotic Burden and High-Sensitive CRP Levels Frequently Do Not Match Framingham Risk Scores in a General Population Raimund Erbel, Stefan Mohlenkamp, Axel Schmermund, Nils Lehmann, Susanne Moebus, Andreas Stang, Dietrich HW Grönemeyer, Rainer RR Seibel, Klaus Mann, Lothar Volbracht, Nico Dragano, Johannes Siegrist, Karl-Heinz Jöckel, on behalf of the Heinz Nixdorf Recall Study Investigators, University Clinic Duisburg-Essen, Essen, Germany, University Clinic Duesseldorf, Duesseldorf, Germany Background: Identiﬁcation and management of presymptomatic CHD based on global risk assessment using the Framingham (FH) score frequently remains uncertain. The extent of subclinical plaque burden (i.e. coronary artery calcium, CAC) and of inﬂammatíon (i.e. hsCRP-levels) is intensively discussed to have a role in risk prediction. In a general population we studied the impact of measuring these parameters on risk stratiﬁcation. Methods: In 4487 subjects without established CHD (45-74 years, 52% women) the FH- score, CAC and CRP were each divided in a low, intermediate and high category. A combined score was derived from CAC- and CRP-values separating subjects into low, intermediate and high CAC+CRP score categories. Results: Mean FH-risk was 11±8. The extent to which the combined CAC+CRP-score modiﬁed risk stratiﬁcation is shown in Fig.1. Up to 6.5% of low FH risk subjects and 16% of intermediate FH risk subjects have a high combined CAC+CRP-score (Fig. 1). In each FH-risk category, several risk factors predisposed to a high CAC+CRP score. These differ between men and women (not shown). Conclusions: Our index of plaque burden with inﬂammation is frequently much higher than anticipated from the FH-risk score. Several risk factors predispose to this mismatch in each FH-risk group. Measuring CAC and CRP allows for identiﬁcation of advanced subclinical coronary atherosclerosis with inﬂammation which may modify risk stratiﬁcation in a substantial number of persons at higher than anticipated risk. 983-208 Stratiﬁcation of Coronary Risk Beyond the Framingham Risk Classiﬁcation: Ultrasound Assessment of Subclinical Disease in a Multiethnic Population Yukio Abe, Tanja Rundek, Robert R. Sciacca, Zhezhen Jin, Ralph L. Sacco, Shunichi Homma, Marco R. Di Tullio, Columbia University, New York, NY Background: Assessment of subclinical cardiovascular disease has been documented to strongly indicate high coronary risk. However, it is uncertain what proportion of subjects may beneﬁt from ultrasound assessment of subclinical disease beyond standard classiﬁcation scales such as the Framingham risk score (FRS). The purpose of this study was to assess the impact of subclinical disease derived from echocardiography and carotid ultrasonography on traditional coronary risk stratiﬁcation using FRS in a community-based multiethnic population. Methods: Echocardiography and carotid ultrasonography were performed in 1,445 community subjects (aged >39 years; 40.0% men; 53.4% Hispanic; 20.5% white; 24.0% black) from the prospective Northern Manhattan Study. Left ventricular mass index (LVMI, g/m2) and maximal carotid plaque thickness (MCPT, mm) were calculated, and left ventricular hypertrophy (LVH) and carotid plaque (CP) were considered as signiﬁcant if LVMI or MCPT was above the gender-speciﬁc 75th percentile. The FRS was calculated based on baseline risk factor characteristics and classiﬁed as low (<10% estimated 10-year coronary risk), intermediate (10-20%) and high (>20%). Subclinical disease was deﬁned as presence of LVH or/and CP, and its prevalence in each FRS category was examined. Results: The proportions of subjects classiﬁed as having low, intermediate, or high FRS were 39.0%, 30.8%, and 30.2% respectively. One-third of the subjects with low or intermediate FRS had subclinical disease (low FRS: 27.4%; intermediate FRS: 40.7%). Black and white subjects with intermediate FRS had a signiﬁcant higher proportion of subjects with subclinical disease than Hispanics with similar FRS (58.8% and 46.3% vs. 31.8%; p <0.0001 and p = 0.019, respectively). Conclusions: Ultrasound assessment of subclinical cardiac and carotid disease may help reclassify over 30% of subjects with low or intermediate FRS into a higher risk group. FRS ACC_2006_8_VascularDisease.indd 338 1/4/06 5:21:17 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 339A Vascular D isease, H ypertension, and P revention appears to underestimate the coronary risk especially in blacks who had a substantially greater prevalence of subclincal disease in the intermediate FRS category. 983-209 Sudden Cardiac Death Risk Prediction is Enhanced When Clinical Characteristics and Left Ventricular Ejection Fraction Are Evaluated Together Rather Than Relying on Left Ventricular Ejection Fraction Alone Brett D. Atwater, Richard N. Vest, Walter R. Mazzei, Jr., Robert H. Tuttle, Sana M. Al- Khatib, Eric Velazquez, Kerry L. Lee, Matthew T. Roe, Duke University Medical Center, Durham, NC, University of Wisconsin Hospitals and Clinics, Madison, WI Background: Left ventricular ejection fraction (EF) lacks sufﬁcient speciﬁcity to be an ideal method of sudden cardiac death (SCD) risk stratiﬁcation. Other clinical characteristics may add predictive power to EF. Methods: Using the Duke Databank for Cardiovascular Disease we identiﬁed 13,612 deceased patients with >74% stenosis of at least one coronary artery on angiography. We created a multivariable logistic regression model to identify clinical characteristics signiﬁcantly associated with SCD or death from other causes. Cause of death was adjudicated by 2 independent investigators. The model was validated via bootstrapping. Results: The median follow-up period was 3.3 years (95% CI 0.7-7.2). 812 patients died of SCD and 12,800 died of other causes. Factors associated with SCD included lower EF, male sex, multi-vessel coronary artery disease (CAD), hyperlipidemia, and hypertension. Older age, COPD, and renal insufﬁciency were associated with death from other causes. The overall model χ2 was 301.7 (p <0.0001, 9 d.f.) The c-index was 0.68 and remained unchanged based on results of the bootstrapping technique. When EF was used as a single predictive variable in a separate model the c-index was 0.59. Table: Factors signiﬁcantly associated with SCD or death from other causes, multivariable analysis. Wald Chi- Square p Value Odds Ratio (95% CI) *Age per 10 years, (patients >60 years old) 61.55 <0.0001 0.61 (0.53-0.69) EF (per 5% decrease) 54.38 <0.0001 1.16 (1.11-1.21) Male sex 29.96 <0.0001 1.62 (1.36-1.93) *COPD 12.53 0.0004 0.58 (0.43-0.79) *Age per 10 years (patients <60 years old) 8.71 <0.0001 0.81 (0.70-0.93) Number of diseased coronary arteries (1, 2, or 3) 6.55 0.011 1.12 (1.03-1.23) *Renal disease 5.96 0.0146 0.41 (0.20-0.84) Hypertension 5.53 0.019 1.21 (1.03-1.41) Hyperlipidemia 4.02 0.045 1.16 (1.00-1.34) *Factors with an Odds Ratio >1 are associated with SCD, factors with an Odds Ratio <1 are associated with causes of death other than SCD. Conclusions: Among patients with CAD, the ability to predict SCD is enhanced when clinical characteristics and EF are evaluated together rather than relying solely upon EF. Consideration of these clinical characteristics in addition to EF may provide a more accurate estimate of overall risk for SCD. 983-210 Gentic Polymorphism G894T Modiﬁes the Smoking- Associated Risk for Myocardial Infarction in Young Individuals Dimitris M. Tousoulis, Charalambos A. Antoniades, Carmen Vasiliadou, Christos Pitsavos, Kyriakoula Marinou, Nikolaos Koumallos, Costas Toutouzas, Gerasimos Siasos, Elli Stefanadi, Christodoulos Stefanadis, Athens University, Athens, Greece Background: Genetic polymorphism G894T on endothelial nitric oxide synthase (eNOS) has been associated with increased cardiovascular risk. This polymorphism has been associated with endothelial dysfunction in high-risk patients and especially in smokers, but not in low-risk individuals. We aimed to examine whether G894T modiﬁes the smoking- associated risk for premature myocardial infarction (MI). Methods: The study population consisted of 228 patients with ﬁrst event of premature MI (aged 46.96±0.4 yrs old) and 519 age- and sex- matched controls. Smokers were deﬁned as those smoking ≥10 cigarettes per day for ≥1 year. “Heavy” smokers were deﬁned as those with ≥20 pack-years and “light” smokers those with <20 pack-years. G894T polymorphism was detected by PCR. Results: The prevalence of smoking was higher in patients (200, 87.7%) compared to controls (301, 57.9%, p<0.001). The frequencies of GG, GT and TT were 97 (42.5%), 99(43.5%) and 32 (14%) in MI and 255(49.1%), 217(41.8%) and 47 (9.1%) in controls. The risk for MI in smokers was 4.623(95%CI:2.936-7.280) p<0.001 compared to non smokers (1.982(1.105-3.738) p=0.034 for “light” and 5.963(3.758-9.462) p<0.001 for “heavy” smokers). Among 894TT, the smoking-associated risk for MI was 13.248(2.655- 66.095) p=0.002 (6.750(0.547-83.231) p=0.136 for “light” and 17.834(3.647-87.215) p=0.001 for “heavy” smokers). Among 894GT, the smoking-associated risk for MI was 4.079(2.047-8.130) p=0.001 (1.790(0.677-4.755) p=0.240 for “light” and 5.176(2.569- 10.430) p<0.001 for “heavy” smokers). In 894GG, the smoking-associated risk was 4.774(2.372-9.612) p<0.001 (2.00(0.729-5.491) p=0.178 for “light” and 6.348(3.102- 12.988) p=0.0001 for “heavy” smokers). The unadjusted risk for MI of 894TT homozygotes in the overall population was 1.640(1.015-2.647) p=0.043 compared to 894GT+GG, and it was elevated to 2.508(1.364-4.611) p=0.003 after exclusion of non-smokers. Conclusions: The G894T polymorphism on eNOS gene increases the smoking- associated risk for premature myocardial infarction, suggesting that 894TT homozygotes are more likely to develop premature myocardial infarction when being smokers, compared to carriers of 894G allele. 983-211 Clinical Implication in Metabolic Syndrome and Ankle-brachial Pressure Index as the Predictor of Cardiovascular Disease Osamu Kuboyama, Takeshi Tokunaga, Hidenobu Takei, Kazuo Kobayashi, Toride Kyoudo General Hospital, Toride, Japan Background: It was reported that people with the metabolic syndrome were at increased risk of coronary artery disease (CAD) and the ankle-brachial pressure index (ABI) provided information about the presence of atherosclerotic cardiovascular disease. We investigated the metabolic syndrome, ABI and other coronary risk factor as the independent predictor of cardiovascular disease truly. Methods: Blood pressure, ABI, body mass index (BMI), fasting glucose (BS), triglyceride (TG), HDL cholesterol and other risk factors were studied in 232 consecutive patients who underwent conventional angiography to diagnose angina pectoris. We used a modiﬁed National Cholesterol Education Program deﬁnition of metabolic syndrome that utilize BMI instead of waist circumference. We evaluated that each risk factor was signiﬁcant for CAD and 3-vessel disease (3VD). Results: Metabolic syndrome was an independent predictor for CAD (p=0.03) but was not an independent predictor for 3VD (p=0.34). ABI < 0.9 was an independent predictor for 3-vessel disease (p=0.01) but was not an independent predictor for CAD (p=0.20). Gender, proteinuria and smoking habit were dominant risk factors for both CAD and 3VD. Aging, HDL cholesterol, TG, BS and serum creatinine were only effective for CAD. Conclusion: Metabolic syndrome was an independent predictor for CAD and ABI was a signiﬁcant marker for severe atherosclerotic cardiovascular disease like 3-vessel disease. Gender, proteinuria and smoking habit were effective risk factors for coronary artery disease. 983-212 Bayesian Application of Highly Sensitive C Reactive Protein Discriminates Risk of Death or Myocardial Infarction Among Simple Clinical Subroups of Patients Following Cardiac Catheterisation Nick Newall, Roger Moore, Paul Browning, Rod H. Stables, Mark Jackson, Cheng hock Toh, Alan Shenkin, David Ramsdale, The Cardiothoracic Centre, Liverpool, United Kingdom, The Royal Liverpool and Broadgreen University Hospital, Liverpool, United Kingdom Background: We sought to apply highly sensitive C reactive protein (hsCRP), clinical variables in risk assessment in contemporary patients following cardiac catheterisation. Method: 2444 patients were prospectively enrolled, followed for up to one year for death or non-fatal myocardial infarction (MI) before revascularisation. Clinical variables and tertiles of hsCRP were compared to outcomes by predeﬁned Cox multivariate regression and Bayesian application of hsCRP among clinical subgroups. Results: 2213 patients had complete data and did not undergo immediate revascularisation. HsCRP > 4.0mg/l marked the cutoff for highest and lower two tertiles of hsCRP. There were 101 (4.6%) deaths or MI. When offered as sole inﬂammatory marker the highest tertile of hsCRP was independently associated with death or MI (HR 1.6 (1.1- 2.4 p=.022)) but did not substantially improve the prognostic performance of multivariate prediction models (area under receiver operator characteristic curve 0.752 for clinical variables alone, 0.757 for clinical variables and hsCRP). Bayesian application of hsCRP tertiles to time to accrue 1, 2.5 and 5% event rates among simple clinical subgroups did usefully discriminate time to event (p<.001 for all bivariate comparisons - see table). Conclusion: hsCRP is of limited value in multivariate risk assessment, but can discriminate high and low risk subsets of patients when applied to simple clinical subgroups. Thus indicating priority while waiting for revascularisation. Time to 1,2.5 and 5% event rates by hsCRP and clinical subgroups Days from enrolment to 1% death or MI Days from enrolment to 1% death or MI Days from enrolment to 2.5% death or MI Days from enrolment to 2.5% death or MI Days from enrolment to 5% death or MI Days from enrolment to 5%death or MI hsCRP<4.0 hsCRP>4.0 hsCRP<4.0 hsCRP>4.0 hsCRP<4.0 hsCRP>4.0 Age>65 65 4 171 34 >365 62 Age<65 217 55 195 6 265 64 LV ejection fraction < 35% 55 2 195 6 265 64 LV ejection fraction 35-50% 23 16 99 45 234 189 LV ejection fraction >50% 163 71 >365 >365 >365 >365 1 vessel > 50% stenosis 142 60 313 170 >365 >365 2 vessels > 50% stenosis 159 36 313 82 >365 >365 3 vessels > 50% stenosis 47 2 85 16 314 45 ACC_2006_8_VascularDisease.indd 339 1/4/06 5:21:18 PM 340A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n ORAL CONTRIBUTIONS 822 Vascular Biology, Atherosclerosis Thrombosis and Endothelium II Monday, March 13, 2006, 2:00 p.m.-3:30 p.m. Georgia World Congress Center, Room B312 2:00 p.m. 822-3 Molecular Dissection of Human LOX-1 Promoter: Nucleotides and Transcription Factors Requirement During Transactivation Jiawei Chen, Hongmei Liu, Yong Liu, Paul Hermonat, Jawahar Mehta, University of Arkansas for Medical Sciences, Little Rock, AR Background: Lectin-like oxidized LDL receptor (LOX-1) is a critical role player in atherosclerosis. LOX-1 expression is upregulated by pro-atherogenic stimuli, such as ox-LDL and Ang II. We examined the molecular mechanisms for LOX-1 promoter transactivation in response to ox-LDL and Ang II in human coronary artery endothelial cells (HCAECs). Methods and Results: In the basal state, LOX-1 core promoter (LOX-1-35/+36 nt) activity was similar to that of the full length LOX-1 promoter (LOX-1-2336/+36 nt). As expected, full length LOX-1 promoter activity was enhanced after treatment with ox-LDL or Ang II, but the LOX-1 core promoter activity was not. With the use of a series of 5’ and 3’ LOX-1 promoter deletion mutants, we identiﬁed that a 105 bp LOX-1 promoter fragment containing the nucleotides -1599 to -1494 (LOX-1-1599/-1494 nt) was necessary for ox- LDL-induced LOX-1 promoter transactivation, whereas a different 116 bp LOX-1 promoter fragment containing the nucleotides from -2247 to -2131 (LOX-1-2247/-2131 nt) was found to be necessary for Ang II-induced LOX-1 promoter transactivation. By EMSA, we identiﬁed the activation of transcription factors Oct-1 and NF-κB in response to ox-LDL and Ang II, respectively. The role of Oct-1 and NF- B was further conﬁrmed by mutagenesis assay. We observed that two site-directed mutations (from “TT to GG”) within the Oct-1 binding motif totally abolished ox-LDL-induced Oct-1 binding as well as the 105 bp LOX- 1 promoter (LOX-1-1599/-1494) transactivation. In contrast, two site-directed mutations (from “GG to TT”) within the NF-κB binding motif abolished Ang II-induced NF-κB binding as well as the 116 bp LOX-1 promoter (LOX-1-2247/-2131) transactivation. Conclusion: This study demonstrates the molecular mechanisms for LOX-1 promoter activation in HCAECs. This study suggests different mechanisms of LOX-1 promoter activation in response to two pro-atherogenic stimuli ox-LDL and Ang II. Whereas Oct-1 appears to play a critical role in ox-LDL-mediated LOX-1 promoter activation, NF-�B is the key player in Ang II-induced LOX-1 promoter transactivation. These observations may have implications in designing drug therapies directed at LOX-1 activation. 2:15 p.m. 822-4 Lectin-like Oxidized LDL Receptor-1 (LOX-1) as a Novel Receptor for Remnant-like Lipoprotein Particles (RLPs) in Vascular Smooth Muscle Cells Yo Aramaki, Noriaki Kume, Hirokazu Mitsuoka, Eri Mukai, Masako Toyohara, Nobuya Inagaki, Toru Kita, Kyoto University, Kyoto, Japan, Kyoto University, Kyoto, Japan Background: Remnant-like lipoprotein particles (RLPs) have been implicated in atherogenesis especially by diabetic dyslipidemia; however, their receptor(s) and effects on vascular cells, especially vascular smooth muscle cells (VSMCs), remain unclear. In this study, we examined if lectin-like oxidized LDL receptor-1 (LOX-1) acts as a receptor for RLPs and its biological effects in VSMCs Methods and Results: RLPs were isolated from human plasma by immunoafﬁnity gel mixture of anti-apolipoprotein A-1 and anti-apolipoprotein B-100 monoclonal antibodies. DiI-labeled RLPs were taken up by CHO-K1 cells stably expressing LOX-1 but not by wild- type CHO-K1 cells. Uptake of DiI-labeled RLPs was competitively suppressed by excess amounts of unlabeled RLPs or oxidized LDL (Ox-LDL), indicating that binding sites for RLPs and Ox-LDL on the LOX-1 molecule are identical or overlapped. RLPs induced LOX-1 expression and cell migration in VSMCs, which were signiﬁcantly suppressed by a neutralizing anti-LOX-1 monoclonal antibody. AG1478, an inhibitor of epidermal growth factor (EGF) receptor phosphorylation, as well as by CRM197 which neutralizes heparin-binding EGF-like growth factor (HB-EGF), also suppressed RLP-induced LOX-1 upregulation and migration of VSMCs, indicating the involvement of HB-EGF shedding. Furthermore, PD98059, SB203580 and wortmannin, inhibitors of extracellular regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K), respectively, signiﬁcantly blocked RLP-induced LOX-1 upregulation and Y27632, a selective inhibitor of Rho kinase (ROCK) signiﬁcantly suppressed RLP- induced cell migration. Conclusions: The present study provides direct evidence, for the ﬁrst time, that LOX-1 is a novel receptor for RLPs in VSMCs. LOX-1-mediated uptake of RLPs upregulates LOX-1 expression and migration of VSMCs through shedding of HB-EGF and subsequent EGF receptor phosphorylation and its down-stream signal transduction including phosphorylation of ERK, p38 MAPK ,PI3K and Rho. LOX-1-mediated uptake of RLPs thus may further enhance vascular dysfunction in atherogenesis. 2:30 p.m. 822-5 Combination of Aspirin and Pravastatin Dramatically Reduces Oxidative Stress and the Expression of LOX-1 and Adhesion Molecules: Novel Insight Into the Mechanism of Action of Aspirin and Statins jiawei chen, hongmei liu, yong liu, paul hermonat, JAWAHAR Mehta, University of Arkansas for Medical Sciences, Little Rock, AR Background: Ox-LDL has been shown to stimulate oxidative stress through its receptor LOX-1. Activation of LOX-1 results in the expression of adhesion molecule in vascular endothelial cells. Both aspirin and stains have previously been shown to reduce the pro- inﬂammatory atherosclerotic state, but only in high supra-therapeutic concentrations. We wondered if aspirin and statin combination would attenuate these parameters of oxidative stress and thereby the pro-inﬂammatory state. Methods and Results: Human umbilical vein endothelial cells (HUVECs) were treated with ox-LDL (60µg/ml, 24 hours). In parallel experiments, HUVECs were pretreated with aspirin (1, 2, 5 mM) or pravastatin (1, 5, 10 µM), or the combination of aspirin (1 mM) and pravastatin (5 µM) followed by ox-LDL treatment. Ox-LDL treatment increased LOX-1 expression, as well as the expression of MCP-1, ICAM-1 and P-selectin. These phenomena were modestly attenuated by aspirin and pravastatin. The combination of aspirin (1 mM) and pravastatin (5 µM) markedly reduced ox-LDL-induced upregulation of LOX-1, MCP-1, ICAM-1 and P-selectin. Treatment of HUVECs with ox-LDL markedly enhanced monocyte adhesion. Whereas pretreatment of cells with aspirin (1 mM) alone or pravastatin (5 µM) alone did not affect ox-LDL-induced monocyte adhesion, the combination of aspirin and pravastatin dramatically reduced monocyte adhesion. Next we examined ox-LDL-induced superoxide anion production, p38 MAPK and NF-κB activation. Again, aspirin (1 mM) or pravastatin (5 µM) alone had no effect, their combination exerted a signiﬁcant inhibitory effect on ox-LDL-induced superoxide anion production, p38 MAPK and NF-κB activation. Conclusion: This study provides strong evidence of a synergistic anti-oxidant effect of aspirin and pravastatin in HUVECs resulting in the inhibition of p38 MAPK and NF-�B activation and reduction in the expression of LOX-1, MCP-1 and adhesion molecules. Inhibition of monocyte adhesion induced by ox-LDL may underlie the salutary effect of aspirin-statin combination in atherosclerosis-related disorders. 2:45 p.m. 822-6 Manganese Superoxide Dismutase Polymorphism Affects the Oxidized LDL-Induced Apoptosis of Macrophages and Coronary Artery Disease Hajime Fujimoto, Minoru Ohno, Seiji Ayabe, Hideki Hashimoto, Hisae Kobayashi, Ryozo Nagai, The University of Tokyo Graduate School of Medicine, Tokyo, Japan, Teikyo University School of Medicine, Tokyo, Japan Background. Apoptosis of vascular wall cells is associated with atherogenesis. Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme localized in mitochondria, and reported to protect macrophages against apoptosis induced by oxidized low density lipoprotein (oxLDL). We investigated the associations of the MnSOD polymorphism (valine-to-alanine in the signal peptide) with the mitochondrial MnSOD (mtMnSOD) activity, with macrophage apoptosis, and with coronary artery disease (CAD). Methods. Blood was taken from 50 healthy subjects (Group 1). Genotype was analyzed by real-time polymerase chain reaction. Leukocyte mtMnSOD activity was measured by inhibition of WST-1. Macrophages were treated with oxLDL (200 µg/ml) for 4 hours and the apoptotic cells stained with annexin were counted. The association of the polymorphism with CAD (deﬁned as having coronary artery lesions with diametric stenosis of 75% or more) was investigated analyzing the genotypes of 828 subjects who underwent coronary angiography (Group 2). Results. MtMnSOD activity of each genotype group in Group 1 was: 71.2 ± 7.1 U/100 cells (alanine/alanine, n = 2), 44.4 ± 4.0 U/100 cells (alanine/valine, n = 12), and 18.9 ± 2.1 U/100 cells (valine/valine, n = 36) (P < 0.0001, non-valine/valine vs valine/valine). After incubation with oxLDL, the percentages of apoptotic macrophages were 48.6 ± 7.6% (alanine/alanine), 70.5 ± 1.5% (alanine/valine), and 89.5 ± 0.9% (valine/valine) (P < 0.0001, non-valine/valine vs valine/valine). Genotype distribution in Group 2 was: alanine/alanine 2.1%, alanine/valine 28.5%, and valine/valine 69.4% (non- CAD group, n=330); alanine/alanine 1.2%, alanine/valine 18.3%, and valine/valine 80.5% (CAD group, n = 498, P = 0.001 by �2 analysis). Multivariate logistic regression analysis revealed the valine/valine homozygote to be an independent coronary risk factor (odds ratio (OR) 1.51; 95% CI (1.04, 2.11); P = 0.030), especially with high plasma LDL levels (≥ 140mg/dl, n = 160) (OR 5.13; 95% CI (1.75, 16.6); P = 0.004). Conclusions. The alanine variant of MnSOD signal peptide increases mtMnSOD activity and protects macrophages against the oxLDL-induced apoptosis, thereby reducing the risk of CAD. 3:00 p.m. 822-7 The CYBA Genotype Is Associated With Altered NADPH Oxidase Activity in Patients With Cardiovascular Disease Shaoshan S. Wang, Payam Mehranpour, Wei Li, Sergey Dikalov, Harland Austin, A. Maziar Zafari, Emory University, Atlanta, GA, Atlanta Veterans Administration Medical Center, Decatur, GA Background: Polymorphisms in the CYBA gene coding for the p22phox subunit of the NAD(P)H oxidase with functional consequences and possible associations with vascular phenotypes have been described in humans. We previously reported a physiological role of the C242T CYBA single nucleotide polymorphism (SNP) with reduced respiratory burst activity in freshly isolated neutrophils from healthy volunteers. In the current study, ACC_2006_8_VascularDisease.indd 340 1/4/06 5:21:18 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 341A Vascular D isease, H ypertension, and P revention we hypothesized that coronary risk factors would alter the relationship between this CYBA SNP and superoxide production in cultured human cell lines from patients with cardiovascular disease. Methods and Results: EBV-transformed lymphoblast cell lines were developed from peripheral blood mononuclear cells of 202 patients undergoing coronary angiography. All patients who agreed to participate in the study provided information about coronary risk factors and medications. Genotypes were determined by real time polymerase chain reaction (PCR) and restriction mapping. Superoxide production was quantiﬁed in cultured lymphoblast cell lines at baseline and upon stimulation with phorbol 12-myristate 13- acetate (PMA) by electron spin resonance (ESR) using the superoxide dismutase (SOD) inhibitable oxidation of the spin probe hydroxylamine 1-hydroxy-3-methoxycarbonyl- 2,2,5,5-tetramethylpyrrolidine (CMH). Picomolar superoxide production per 106 resting lymphoblasts per minute for the CC (n=74), CT (n=88), and TT (n=33) genotypes were 15.97±1.31, 12.16±1.30, and 11.88±0.32 respectively (P<0.005). In contrast, the A640G and the -930A/G SNPs did not affect superoxide production (P>0.2). Conclusions: The presence of the CC genotype of the CYBA C242T SNP is associated with signiﬁcantly increased NADPH oxidase activity in human lymphoblast cell lines, independent of coronary risk factors for atherosclerosis. Since p22phox exists in both the lymphoblasts and vessel wall, vascular oxidative stress is likely altered in individuals with this SNP. Finally, a highly sensitive in vitro measurement of superoxide in human cell lines will allow investigators to study genotype/phenotype interactions of candidate genes of oxidative stress with NADPH oxidase activity. 3:15 p.m. 822-8 Synergistic Effect of Cytochrome P450 Epoxygenase CYP2J2 G-50T Polymorphism With Smoking on the Onset of Premature Myocardial Infarction Ping-Yen Liu, Yi-Heng Li, Jyh-Hong Chen, Hua-Lin Wu, Liang-Miin Tsai, Li-Jen Lin, National Cheng Kung University Medical Center, Tainan, Taiwan,ROC Background: Cytochrome P450 (CYP) 2J2 is expressed in the vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs), which are potent endogenous vasodilators and inhibitors of vascular inﬂammation. Our study aim is to elucidate a functional CYP2J2 promoter G-50T polymorphism and smoking for the onset of premature myocardial infarction (MI). Methods: We studied 200 consecutive patients with acute MI onset at age under 45 years (84% men) and 200 sex- and age-matched control subjects. CYP2J2 G-50T polymorphism was determined using PCR and DNA direct sequencing. Results: The prevalence of GT+TT genotype was signiﬁcantly higher in premature MI group (28.0 vs. 22.0%, p=0.01). Multiple logistic regression analysis showed that the T allele was an independent risk factor (OR 1.78, 95% CI 1.1-6.4, p=0.02), as well as smoking (OR 3.05, 95% CI 1.6-7.3, p<0.01), diabetes mellitus (OR 3.24, 95% CI 1.2- 6.6, p<0.01) and hypertension (OR 1.95, 95% CI 1.1-5.7, p<0.01) for the premature MI. Among patients who did not smoke, the T allele was associated with a 1.4-fold higher risk, but smoking carriers with T allele had a 5.6-fold higher risk for MI. The EETs metabolites were signiﬁcantly lower among T allele phenotype MI patients (6.2±1.2 vs. 10.8±2.5 ng/mL, p=0.025). Smoking could further lower the EETs concentrations among T allele carriers (3.3±1.0 vs. 6.8±1.3 ng/mL, p=0.001). Conclusion: There was a signiﬁcant association between CYP2J2 G-50T polymorphism and premature MI in Taiwan. A synergistic effect between smoking and this polymorphism for the premature onset of MI had been shown in this study. ORAL CONTRIBUTIONS 823 Vascular Pathophysiology: Basic and Angiogenesis/Gene Therapy I Monday, March 13, 2006, 4:00 p.m.-5:00 p.m. Georgia World Congress Center, Room B206 4:00 p.m. 823-3 Improvement of Left Ventricular Function With Intramyocardial Injections of Hepatocyte Growth Factor Naked DNA Plasmid in Dogs With Heart Failure Is Associated With Normalization of Cardiac Sarcoplasmic Reticulum Calcium Cycling Proteins Sudhish Mishra, Makoto Imai, Sharad Rastogi, Ramesh C. Gupta, Sanjaya Khanal, Alice J. Jiang, Sidney Goldstein, Hani N. Sabbah, Henry Ford Health System, Detroit, MI Background: We previously showed that intramyocardial injections of naked plasmid encoding human hepatocyte growth factor (HGF) into the LV anterior wall (AW) of dogs with microembolization-induced heart failure (HF)improved systolic shortening of the AW. This study examined the effects of HGF injections on sarcoplasmic reticulum (SR) calcium cycling proteins using LV tissue from the LV AW and LV posterior wall (PW) of the same cohort of dogs. Methods: LV AW and LV PW tissue was obtained from 7 HF dogs treated with 10-15 injections of HGF in AW (total of 4.0 mg), 7 HF control dogs treated with 10-15 injections of saline in AW (equal volume) and 7 normal (NL) dogs 3 months after initiating therpay. Tissue was used to extract RNA and to prepare homogenate. mRNA expression for phospholamban (PLB), SERCA-2a and ryanodine receptors (RYR) was measured using reverse transcriptase polymerase chain reaction (RT-PCR) and protein expression was measured in tissue homogenate by Western blotting. Bands were quantiﬁed in densitometric units (du). Results: Data shown in the table. Compared to NL, mRNA and protein expression of PLB, SERCA-2a and RYR decreased signiﬁcantly in the LV AW and LV PW of HF control dogs but normalized only in the LV AW after HGF therapy. Conclusions: In HF dogs, intramyocardial injections of HGF into the LV AW normalized SR calcium cycling proteins. This observation is consistent with the observed improvement in regional LV wall function of dogs with HF after treatment with naked plasmid encoding human HGF. mRNA and Protein Expression (du) LV AW LV PW NL HF-Control (+Saline) HF+HGF NL HF-Control (No Saline) HF (No HGF) PLB mRNA 417 ± 29 183 ± 8* 534 ± 10*^ 310 ± 13 109 ± 3* 184 ± 9*^ SERCA-2a mRNA 101 ± 4 49 ± 2* 117 ± 4* 109 ± 4 49 ± 2* 53 ± 2* RYR mRNA 479 ± 10 44 ± 3* 381 ± 23*^ 513 ± 15 58 ± 3* 67 ± 3* PLB Protein 12 ± 0.5 8 ± 0.4* 10 ± 0.3*^ 12 ± 0.5 10 ± 0.2* 11 ± 0.3*^ SERCA-2a Protein 644 ± 96 296 ± 56* 598 ± 68^ 136 ± 7 99 ± 9* 119 ± 2 RyR Protein 179 ± 4 145 ± 7* 174 ± 5^ 131 ± 8 86 ± 8* 96 ± 4* *=p<0.05 vs. NL; ^=p<0.05 vs. HF-Control 4:15 p.m. 823-4 Induction of Heart and Smooth Muscle-Speciﬁc Genes in Human Mesenchymal Stem Cells and Epicardium- Derived Cells After Forced Myocardin Expression John van Tuyn, Shoshan Knaän-Shanzer, Antoine A. de Vries, Arnoud van der Laarse, Adriana C. Gittenberger-de Groot, Martin J. Schalij, Ernst E. van der Wall, Douwe E. Atsma, Leiden University Medical Center, Leiden, The Netherlands, Interuniversitary Cardiological Institute the Netherlands, Utrecht, The Netherlands Background: We studied the potential of the transcription factor myocardin to induce cardiac and smooth muscle gene expression in bone marrow-derived mesenchymal stem cells (MSCs) and epicardium-derived cells (EPDCs) from human adults, with the ﬁnal goal of enhancing their differentiation into cardiomyocytes for transplantation purposes. Methods & Results: In vitro expanded EPDCs resemble MSCs in morphology and surface marker expression. However, unlike MSCs, EPDCs could only be differentiated into osteoblasts, but not adipocytes in vitro, using standard differentiation procedures. EPDCs but not MSCs also express the cardiac marker genes GATA4 and cardiac troponin T (cTnT). One week after transduction with an adenovirus vector encoding human myocardin or a control vector, gene expression in both cell types was analysed by RT- PCR and immunoﬂuorescence microscopy (IFM). Forced myocardin expression, led to the activation of the atrial and ventricular myosin light chain 2, alpha-myosin heavy chain (alpha-MHC), atrial natriuretic factor, SERCA2a and eHand genes in both cell types, and of GATA4 and cTnT in MSCs. In addition to the activation of heart muscle-speciﬁc genes, myocardin also induced expression of the smooth muscle-speciﬁc genes smooth muscle myosin heavy chain (smMHC), aortic smooth muscle actin, calponin h1 and SM22 in MSCs and EPDCs. Neither of these cell types expressed cardiac troponin I or Nkx2.5 under any condition. Interestingly, IFM revealed that in the presence of exogenous myocardin only 10% of the MSCs, but virtually 100% of the EPDCs stained positive for cardiac myosin and actinin, SERCA2a and the smooth muscle protein smMHC. Conclusions: Our ﬁndings demonstrate that myocardin activates a wide range of heart muscle genes and the highly speciﬁc smooth muscle marker gene smMHC in both cell types, underscoring that myocardin plays an important role in both smooth and cardiac muscle development. The difference in myocardin responsiveness between EPDC and MSC cultures may indicate that additional regulatory factors, present in all EPDCs but only in a subfraction of MSCs, are required for heart and/or smooth muscle gene activation. 4:30 p.m. 823-5 Local Delivery of Bone Marrow Derived Stromal Cells Engineered to Overexpress Prostacyclin Synthase Enhanced Collateral Perfusion in Hindlimb Ischemia Yasushi Numaguchi, Masakazu Ishii, Ryuji Kubota, Kazuhiko Yokouchi, Yasuhiro Ogawa, Kenji Okumura, Toyoaki Murohara, Nagoya University, Nagoya, Japan Bone marrow cell therapy contributes to collateral formation through cell incorporation into vessels and secretion of angiogenic cytokines like HGF, VEGF, and MCP-1 in a paracrine manner. Prostacyclin is a vasculoprotecive and proangiogenic prostanoid. Although combined gene therapy with naked plasmids of prostacyclin synthase (PGIS) and HGF showed efﬁcacy in hindlimb ischemia models, the efﬁciency of marrow derived stromal cells (MSCs) engineered to overexpress PGIS is unknown. We tested hypothesis that cell therapy with MSC overexpressed PGIS would have superior efﬁciency in recovery from hindlimb ischemia to the delivery of either PGIS gene or MSC alone. Methods and Results: Murine MSC was harvested by ﬂushing femurs and transfected with adenoviral vector encoding GFP alone or GFP and PGIS (AdGFP and AdBiG+P; 150 MOI each). Cell cycle analysis assessed by FACS revealed that there was no signiﬁcant difference between MSCs overexpressed GFP alone and GFP+PGIS in both apoptosis rate and DNA synthesis (n=3 each). C57/BL6J mice received gene or MSC injection to the adductor muscle 1 day after femoral artery liagation. Mice were divided into 4 groups (n=8 each) following injected content; vehicle, AdBiGP(AdG+P, 4x109 PFU), MSC with AdGFP (MG), and MSC with AdBiG+P(MG+P) (MSC;1x106 cells/250ÂµL each). Laser Doppler Perfusion Imaging demonstrated increased blood ﬂow recovery in mice of MG and MG+P ACC_2006_8_VascularDisease.indd 341 1/4/06 5:21:19 PM 342A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n groups (Ischemic/Non ischemic limb at 1, 2, 3 weeks; p<0.01 vs control) and MG+P mice reached to peak blood ﬂow by 10 days after surgery earlier than MG (p<0.05), while AdG+P group had no signiﬁcant blood ﬂow increase with edema in the legs. This resulted in reduced calf muscle atrophy and ﬁbrotic tissue content and increased capillary density in the groups of MG and MG+P. In mice of MG+P, collateral formation at 2 weeks was accelerated than MG mice (p<0.05). Conclusion: Local delivery of MSC overexpressed PGIS would be a novel therapy for peripheral artery disease. 4:45 p.m. 823-6 Regulation of Endothelial Progenitor Cell (EPC) Survival and Vasculogenesis by Peroxisome Proliferator-activated Receptor-Delta (PPAR-δ) Activation Jung-Kyu Han, Hee-Kyung Lee, Han-Mo Yang, Jin Hur, Hyun-Jae Kang, Woo-Young Chung, Bon-Kwon Koo, Yong-Jin Kim, Dae-Won Sohn, Byung-Hee Oh, Young-Bae Park, Yun-Shik Choi, Hyo-Soo Kim, Cardiovascular Center, Seoul National University Hospital, Seoul, South Korea, Cardiovascular Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, South Korea Background:PPARs form a subfamily of the nuclear receptor superfamily and three isoforms, PPAR- α, -γ, -δ, have been identiﬁed thus far. Because of its ubiquitous expression and the paucity of selective ligands, PPAR-δ is the least understood PPAR subtype. Recent data showed that PPAR-γ activation induces apoptosis of endothelial cell (EC) and inhibits angiogenesis. However, the role of PPAR-δ on EC or EPC is nearly unknown. Thus we investigated the role of PPAR-δ on EPC in terms of cell survival and vasculogenic potential. Methods & Results:Human EPCs were cultured under the variable concentration of GW501516, a potent and selective PPAR-δ agonist. GW501516 enhanced EPC proliferation, and inhibited apoptosis dose dependently both in trypan blue exclusion assay and in cell cycle and apoptosis FACS. In matrigel tube formation and transendothelial migration assay, tube formation and migration of EPC were enhanced in proportion to GW501516 concentration. GW501516 also increased secretion of angiogenic cytokines, VEGF and IL-8 from EPC. Expression of surface markers of EC such as CD31 and VE-cadherin was increased under GW501516, suggesting differentiation of EPC to EC lineage. To verify the effects of PPAR-δ activation in vivo, mouse hindlimb ischemia model was used. GW501516- treated or non-treated EPC were locally injected into ischemic limb. Mice injected with treated EPC showed improved perfusion to ischemic limb and less limb loss compared with those with non-treated EPC (n=30, p<0.05). The ﬁnding that GW501516 increased phosphorylation of Akt in EPC suggested the role of PI3K/Akt signaling in mediating PPAR- δ effects. Blocking experiment with PI3K blocker, LY294002, abolished the aforementioned several effects of PPAR-δ activation on EPC, conﬁrming the role of PI3K-Akt. Conclusions: PPAR-δ activation enhanced survival, inhibited apoptosis and increased differentiating potential of EPC. PPAR-δ signiﬁcantly improved vasculogenic potential of EPC both in vitro and in vivo. Those effects of PPAR-δ activation were mediated via PI3K/Akt pathway. The results of our study implicate possible role of PPAR-δ agonists in treatment of cardiovascular disease including ischemic heart disease. ORAL CONTRIBUTIONS 835 Hypertension: Target Organ Damage Tuesday, March 14, 2006, 7:00 a.m.-8:30 a.m. Georgia World Congress Center, Room B312 7:00 a.m. 835-3 Role of Volume Load in Heritability of Left Ventricular Mass: The Hypergen Offspring Study Giovanni de Simone, Weihong Tang, Donna K. Arnett, Dabeeru C. Rao, Dalane W. Kitzman, Steven C. Hunt, Jonathan N. Bella, Richard B. Devereux, Weill Medical College, New York, NY Background: Left ventricular (LV) mass (M) and 24-h urinary Na+/K+ ratio predict development of arterial hypertension in healthy adults (Ann Intern Med 1991), suggesting that increased circulatory volume can interact with greater muscle size in the cardiovascular system to promote development of hypertension. We assessed whether part of genetic heritability of LV mass can be explained by stroke volume inheritance. Methods: Height-normalized echocardiographic LV mass, stroke volume (SV, by Doppler echocardiography) and peripheral resistance, were measured in 1792 subjects without prevalent cardiovascular disease or diabetes, from 531 families with more than 3 relative pairs (sibs and parent:child pairs) from the HyperGEN offspring study (51% African-American, 43% males, 44% obese, 53% hypertensive). Genetic correlations were estimated using a variance components procedure (SOLAR). Results: After adjusting for age, sex, race, ﬁeld center, systolic blood pressure (BP), number of antihypertensive medications and body mass index (BMI), heritability of LVM was greater (h2=0.51, SE=0.06, p<0.0001) than for SV (h2=0.15, SE=0.06, p<0.003). Signiﬁcant genetic correlations were detected among LVM and SV, after adjusting for age, sex, race and ﬁeld center (rG=0.62, SE=0.11, p<0.0001) and were maintained after further adjustment for systolic BP, antihypertensive therapy and BMI (rG=0.46, SE=0.14, p<0.005). Heritability of LVM was not reduced when SV was added as a covariate (h2=0.52, SE=0.06, p<0.0001), but heritability of SV was slightly reduced when LVM was added as a covariate (h2=0.12, SE=0.05, p<0.02). Peripheral resistance was moderately heritable after covariate adjustment (h2=0.20, SE=0.06, p<0.0001), and was not inﬂuenced by adding SV into the model. Conclusions: A strong heritability is found for LVM, which is not affected by adjustment for SV. Similarly, heritability of SV is only marginally inﬂuenced by heritability of LVM, suggesting that volume component of cardiovascular load and inherited development of cardiovascular musculature each are mainly inﬂuenced by its own genetic factors. An independent heritability is also detectable for peripheral resistance. 7:15 a.m. 835-4 Gender Differences in Pressure Wave Reﬂection Changes With Healthy Aging: A Population-Based Study in Hispanic Mestizos Julio A. Chirinos, Joseﬁna Medina-Lezama, Humberto Zea-Diaz, Oscar Morey-Vargas, Juan F. Bolanos, Mauricio Postigo-Mac Dowall, Edgar Munoz-Atahualpa, Paola Villalobos, Shirley Paredes, Blanca Zevallos-Buscalla, Julio Chirinos-Pacheco, Santa Maria Catholic University School of Medicine, Miami, FL Background: Systolic augmentation of aortic pressure is a manifestation of wave reﬂection and is inﬂuenced by arterial stiffness. Age-related changes in augmentation index (AI) have not been studied in Hispanics. Methods: We studied 556 Mestizo Hispanic individuals without cardiovascular disease, diabetes, hypertension or hypercholesterolemia as part of a population-based study. Aortic arterial waveforms were obtained with radial applanation tonometry and a validated transfer function. AI was calculated as the difference between the second and ﬁrst systolic peaks, expressed as a percentage of pulse pressure. Results: AI was signiﬁcantly higher in women than men (23.5±11% vs. 12.9±13%; p<.0001) and demonstrated a strong direct correlation with age in both males and females. This relation was non-linear due to an attenuation in the age-related increase in AI with older age, as demonstrated by a signiﬁcant negative age squared term (Figure). This attenuation was more pronounced in females, resulting in a decrease in the gender difference in AI with older age. These observations persisted after adjusting for mean arterial pressure, heart rate and body height. Conclusions: Our study shows a clear age-related increase in central AI in Hispanic Mestizos which is attenuated with increasing age. In contrast to Caucasians, AI continued to increase until the the 8th decade of life in healthy males and females. Furthermore, our study shows important gender differences in changes in AI with healthy aging. 7:30 a.m. 835-5 Brain Natriuretic Peptide Gene Polymorphism (C+171A) Is Associated With the Presence of Left Ventricular Hypertrophy Anekwe E. Onwuanyi, Qing Song, Alexander Quarshie, Adeﬁsayo Oduwole, Rigobert Lapu-Bula, Clifford Thomas, Elizabeth Oﬁli, Morehouse School of Medicine, Atlanta, GA Background: Left ventricular hypertrophy (LVH) is a major complication of hypertension that is associated with increased cardiovascular morbidity and mortality. Brain Natriuretic Peptide (BNP), synthesized by the cardiac myocytes predominantly in the ventricles and secreted in response to left ventricular wall stretch is elevated in individuals with hypertension and LVH. The serum level of BNP appears to correlate more with the degree of LVH than with mean arterial blood pressure. Recent studies suggest that BNP also suppresses LVH indicating its role both as a marker and modulator of LVH. Thus, the hemodynamic burden of hypertension is not the sole determinant of LVH. We hypothesize that variation in the BNP gene expression is associated with susceptibility to LVH. Method: Two hundred and thirteen subjects participating in a National Institute of Health sponsored study on endothelial function were enrolled in this study. Three common single nucleotide polymorphisms (SNPs) were identiﬁed with TagSNP. The polymorphism investigated were A-2255G, C-2193G and C+171A. Genotyping was carried out on a Pyrosequencer PSQ96MA, (Pyrosequencing Inc, Uppsala, Sweden). Results: One hundred and thirty eight subjects (64%) were women, 132 (62%) were hypertensive and 37 (17.4%) had echocardiographic LVH. The mean age of the hypertensive and normotensive groups were 49.0 ± 10.67 years and 43 ± 9.40 years respectively. ACC_2006_8_VascularDisease.indd 342 1/4/06 5:21:19 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 343A Vascular D isease, H ypertension, and P revention The C+171A allele was found to be signiﬁcantly associated with LVH in the overall study population, p=0.007. Stratifying by hypertension, this relationship was marginally signiﬁcant among hypertensive group (p=0.06) and borderline signiﬁcant among normotensives (p=0.05). The BNP gene alleles A-2255G and C-2193G were not related to LVH. Conclusion: The C+171A single nucleotide polymorphism (SNP), located in exon 1 of the BNP gene is a missense SNP that causes Arginine (CGT) 25 Leucine (CTT) mutation. Its presence may indicate susceptibility to LVH. Further studies are warranted to determine how this genetic variant affects BNP secretion and modulates the hypertrophic response to hypertension. 7:45 a.m. 835-6 Increased Pulse Pressure is Strongly Associated with Adverse Cardiovascular Outcomes in both Diabetics and Non Diabetics: The International Verapamil SR- Trandolapril Study (INVEST) Sripal Bangalore, Franz H. Messerli, Stanley Franklin, Giuseppe Mancia, Ann Hewkin, Annette Champion, Carl J. Pepine, INVEST Investigators, St Lukes Roosevelt Hospital, New York, NY, University of Florida, Gainesville, FL Background: Increasing pulse pressure (PP) is an independent predictor for cardiovascular disease in elderly subjects with essential hypertension. However, the relationship between increasing PP and cardiovascular disease is less well deﬁned in diabetics vs. non diabetics. Methods: We evaluated 6400 diabetic (66±9 years, 54% women) and 16,176 non diabetic (66±10 years; 51% women) CAD patients with hypertension enrolled in the INVEST trial who were randomized to verapamil SR (Ve) or atenolol (At) strategies and followed for 2.7 years (mean). Primary outcome (PO) was time to ﬁrst occurrence of death (all cause), nonfatal MI or nonfatal stroke. PP at entry and on treatment was calculated and summarized by 5 mm Hg subgroups for association with PO. Results: At 2 yrs, the Ve and At strategies had comparable BP control (71.7 vs 70.7% for BP <140/<90 mm Hg, P=0.18). Incidence of the PO was equivalent between Ve and At strategies (9.9 vs 10.2%, HR = 0.98, CI = 0.90, 1.06). Increased PP was associated with increased incidence of the PO in both diabetic and non diabetic patients. For each PP category, diabetics had a signiﬁcantly higher incidence of PO than non diabetics (graph). Conclusion: In CAD patients with hypertension, increasing pulse pressure is a powerful risk factor for adverse CV outcomes among both diabetic and non diabetic patients. For each pulse pressure category, diabetics have a higher incidence of adverse CV outcomes compared to non diabetics. 8:00 a.m. 835-7 Effects of Optimal Versus High Normal Blood Pressure on Progression of Coronary Atherosclerosis: Insight From the CAMELOT Study Ilke Sipahi, E. Murat Tuzcu, Stephen J. Nicholls, Okan Gulel, Katherine E. Wolski, David J. Frid, Harry Shi, Samir Kapadia, Paul Schoenhagen, Steven E. Nissen, The Cleveland Clinic Foundation, Cleveland, OH Background: The effect of high normal blood pressure (BP) on progression of coronary atherosclerosis is unknown. Our aim was to evaluate this by serial intravascular ultrasound (IVUS). Methods: Patients enrolled in the IVUS substudy of the Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT) trial were included (n=274). Eligibility criteria were angiographically documented coronary disease and diastolic BP (DBP)<100 mmHg. Patients underwent IVUS of a single coronary artery, which was repeated after 2-years of treatment with amlodipine 10 mg/day, enalapril 20 mg/day, or placebo. Progression rate of atherosclerosis was measured as the change in total atheroma volume (TAV), which was compared according to different on-treatment BP levels. Results: Mean BP throughout the study was 127.1±12.2/75.5±6.6 mmHg. Change in TAV was signiﬁcantly higher in patients with systolic BP (SBP) levels >140 mmHg, as well as in those with SBP between 125-140 mmHg, as compared to those with SBP<125 mmHg, who actually had regression of disease (Figure). DBP levels were unrelated to change in TAV. Conclusions: To slow progression of coronary atherosclerosis an SBP level of <125 mmHg is more favorable than an SBP within the high-normal (or prehypertensive) range. This IVUS study supports the epidemiological evidence showing continual risk reduction with lower BP levels. In patients with coronary artery disease, target BP may be lower than the 140/90 mmHg level advocated in the current guidelines. 8:15 a.m. 835-8 Inappropriate Left Ventricular Mass Identiﬁes Hypertensive Patients With High-Risk Cardiac Phenotype Marcello Chinali, Carmela Romano, Gianpaolo D’Addeo, Margherita Benincasa, Marina De Marco, Maurizio Galderisi, Giovanni de Simone, Federico II University Hospital, Napoli, Italy Background: Left ventricular (LV) mass (M) exceeding levels needed to compensate hemodynamic load has been termed “inappropriate LV mass”(iLVM). iLVM is associated with concentric LV geometry and reduced LV systolic and diastolic function. We hypothesized that iLVM identiﬁes hypertensive patients with clustered cardiac geometric and functional abnormalities better than LV hypertrophy (H). Methods: 359 hypertensive (45±11 years, 125 women) and 165 normotensive individuals (32±11 years, 110 women) without prevalent cardiovascular disease underwent standard Doppler echocardiography. Observed LVM exceeding 128% of the value predicted for individual cardiac work, body size and gender was deﬁned as iLVM. Concentric LV geometry was deﬁned as age-adjusted relative wall thickness (RWT) >0.40. Systolic dysfunction was deﬁned as ejection fraction <0.50 and/or midwall shortening <14.7% (10th percentile of reference population). Diastolic dysfunction was deﬁned as isovolumic relaxation time (IVRT) >100msec, E-wave deceleration time >220msec and/or age-adjusted E/A ratio <0.66. LVH was deﬁned as LVM/ht2.7>49.2g/m2.7in men and >46.7g/m2.7in women. Results: Hypertensive patients showed a 23.4% prevalence of iLVM and 39.4% prevalence of LVH. iLVM was associated with higher RWT, lower LV systolic function, longer IVRT and prolonged E-deceleration time (all p<0.05). Compared to patients with traditionally deﬁned LVH, patients with iLVM had higher prevalence of concentric geometry (65.5% vs 40.4%), systolic dysfunction (67.9% vs 47.4%) and diastolic dysfunction (46.4% vs 39% ;all p<0.001). Compared to LVH, classiﬁcation for appropriateness of LVM had higher sensitivity (0.82 vs 0.57) and speciﬁcity (0.89 vs 0.62; both p<0.01) for identiﬁcation of hypertensive patients with clustered LV geometric and functional (both systolic and diastolic) abnormalities. Conclusions: iLVM is signiﬁcantly associated with concentric geometry, delayed LV relaxation and reduced systolic performance. Compared to traditional deﬁnition of LV hypertrophy, the presence of iLVM is more accurate in identifying patients with high-risk cardiac phenotype. POSTER SESSION 1000 Anatomic and Functional Aspects of Arterial Function Tuesday, March 14, 2006, 8:30 a.m.-Noon Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 1000-159 Impaired Nitrate-Mediated Dilatation Could Reﬂect Nitrate Tolerance and Predicted Need of Revascularization Rui Hu, Pui Yee Lee, Chu Pak Lau, Elizabeth OY Lau, Hung Fat Tse, Queen Mary Hospital, Hong Kong, Hong Kong, Hong Kong University, Hong Kong, Hong Kong Background: Nitrate mediated dilatation (NMD) of brachial artery can be impaired in patients (pts) with coronary artery disease (CAD). However, its association with nitrate tolerance and clinical outcomes remains unclear. Methods: A total of 243 pts (mean age 61± 12 years, 146 male) were recruited before coronary angiography. Gensini score was calculated to assess the severity of CAD. NMD and ﬂow-mediated dilation FMD of brachial artery were measured. Results: NMD progressively decreased (16.2±6.01% versus 13.4±5.57% versus 9.57±4.52 %, all P<0.001) from pts without CAD ( n=71) to non-nitrate users(n=64) and nitrate users (n=108) with CAD.Multiple linear regression showed that only age, FMD, diameter of brachial artery, hypertension, and nitrate use were independent determinants of NMD. During a median of 16 months follow-up, a total of 67 pts experienced 33 cardiovascular ACC_2006_8_VascularDisease.indd 343 1/4/06 5:21:20 PM 344A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n events (death, acute coronary syndrome and stroke) and 49 revascularization. Multivariate Cox-regression showed that only impaired NMD≤12 % predicted the need of revascularization (HR 2.61, 95 %CI: 1.25-5.46), independent of nitrate use and Gensini score. The impaired FMD≤4.5 % (HR: 3.50, 95% CI: 1.33- 9.18) and nitrate use (HR: 5.42, 95%CI: 1.64-17.9) independently predicted spontaneous cardiovascular events. Conclusions: Impaired NMD could reﬂect status of nitrate tolerance, and predicted the need of revascularization; while impaired FMD and nitrate use predicted spontaneous cardiovascular events independently . NMD Independently Impaired by Nitrate Use Nitrate users (n=46) Non-nitrate users (n=18) Age (yrs) 65 ±11 65 ±12 Hypertension 29(63%) 12(67%) Gensini score 23.1±1.32 22.2±1.48 Diameter of Brachial Artery (mm) 3.96±0.66 3.86±0.51 FMD % 2.71±3.29 3.70±2.64 NMD % 8.59±3.47 13.2±5.28* *P<0.05, comparison by t test in pts with 3-vessel coronary disease 1000-160 Lipoprotein-Associated Phospholipase A2 is an Independent Marker for Coronary Endothelial Dysfunction in Humans Eric H. Yang, Joseph P. McConnell, Ryan J. Lennon, Gregory W. Barsness, Geralyn Pumper, Stacy J. Hartman, Charanjit S. Rihal, Lilach O. Lerman, Amir Lerman, Mayo College of Medicine, Rochester, MN Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is involved in the metabolism of oxidized phospholipids and is a predictor of coronary heart disease. Objectives: To determine if Lp-PLA2 is associated with coronary endothelial dysfunction and is a predictor of endothelial dysfunction in humans. Methods: 172 patients with no signiﬁcant coronary artery disease (>30% stenosis) were studied. Endothelial function was assessed by the change in coronary blood ﬂow and coronary artery diameter in response to intracoronary acetylcholine. Plasma concentrations of Lp-PLA2 were measured and patients were divided into tertiles. Results: Patients in tertiles 2 and 3 had a signiﬁcantly lower change in coronary blood ﬂow and greater epicardial coronary artery vasoconstriction in response to acetylcholine. These ﬁndings remained signiﬁcant after adjusting for age, sex, body mass index, creatinine (log-transformed), total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides (log-transformed), and use of lipid lowering medication. Patients with coronary endothelial dysfunction had a signiﬁcantly higher serum concentration of Lp- PLA2 than normals (246.2 ± 71.6 versus 209 ± 56.7 ng/ml, p = 0.001). The odds ratio for coronary endothelial dysfunction in patients with Lp-PLA2 in the highest tertile was 3.3 (95% CI1.6-6.6). Conclusions: Lp-PLA2 is independently associated with coronary artery endothelial dysfunction and a strong predictor of endothelial dysfunction in humans. 1000-161 Does the Presence of a Depressive State Contribute to Endothelial Dysfunction in Patients With Coronary Artery Disease? Hiroki Teragawa, Kentaro Ueda, Junko Soga, Kenji Nishioka, Noboru Oda, Hiroshi Ogi, Miwa Miyoshi, Yukiko Nakano, Yukihito Higashi, Masao Yoshizumi, Tetsuya Oshima, Kazuaki Chayama, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan Background: An inverse association between depression and poor prognosis of coronary artery disease (CAD) has been observed in several epidemiological studies. Although some possible mechanisms have been proposed, it is unknown whether endothelial dysfunction is involved in the mechanisms for depression-related cardiovascular events in patients with CAD. We investigated the relationship between a depressive state and endothelial function in the brachial artery of patients with CAD. Methods: Seventy-seven patients (mean age 63 years) with CAD, who had >50% stenosis of the major coronary arteries on the coronary angiogram were evaluated. Patients were diagnosed as being in a depressive state when their Zung Self-Rating Depression Scale score was >40. The patients were divided into two groups based on whether they were in a depressive state of any degree (Group I) or not (Group II). In each patient, changes in the diameter of the brachial artery in response to hyperemic ﬂow (ﬂow-mediated dilatation: FMD) and nitroglycerin spray (NTG) were measured using high resolution ultrasonography. Results: Twenty-three were in a depressive state (Group I). There was a higher percentage of women in Group I (43% vs. 13% in Group II, p = 0.0043). Hypertension was less frequently observed in Group I (60% vs. 83% in Group II, p = 0.0383). FMD was lower in Group I than in Group II (3.8±0.9% vs. 6.3±0.6%, p = 0.0190) while NTG-induced dilation was similar in the two groups (14.0±1.2% vs. 14.6±0.8%, NS). Multivariate regression analysis demonstrated that the presence of a depressive state (p = .0152) as well as NTG-induced dilation (p = .0499) inﬂuenced the FMD. Conclusions: These ﬁndings suggest that the presence of a depressive state was associated with endothelial dysfunction in patients with CAD. Thus, the presence of depression may contribute to increase the risk of cardiovascular events mediated, in part, by endothelial dysfunction. 1000-162 Small HDL Particles Exert Potent Protection of Human Endothelial Cells Against Apoptosis: Relevance to Metabolic Syndrome Juliana A. de Souza, Cecile Vindis, Sandrine Chantepie, Anne Nègre Salvayre, Robert Salvayre, M. John Chapman, Anatol Kontush, INSERM Unit 551, Paris, France, INSERM Unit 466, Toulouse, France Background: Oxidized low density lipoprotein (oxLDL) induces endothelial cell apoptosis and necrosis. Plasma high density lipoprotein (HDL) exerts potent anti-apoptotic activity. HDL subfractions are heterogeneous on a physicochemical basis; the potential heterogeneity of the anti-apoptotic activity of HDL is indeterminate. Methods: Five major HDL subfractions (HDL2b, 2a, 3a, 3b, 3c) were fractionated from serum by density gradient ultracentrifugation. Human microvascular endothelial cells (HMEC) were incubated with mildly oxLDL (200 µg apoB/ml) in the presence or absence of each HDL subfraction (5-100 µg protein/ml). Results: All HDL subfractions isolated from normolipidemic subjects protected HMEC against oxLDL-induced apoptosis as demonstrated by ﬂuorescent nucleic acid staining (Syto13/PI), annexin V binding, quantitative DNA fragmentation, inhibition of caspase-3 activity and reduction of cytoplasmic release of cytochrome c and of apoptosis-inducing factor. At equal protein concentrations, small, dense HDL3c and 3b subfractions (60 and 43% protection in the MTT test, respectively) possessed more potent anti-apoptotic activity as compared to large, light HDL2a (29%) and 2b subfractions (25%; p<0.001 vs. HDL3c). All HDL subfractions attenuated generation of reactive oxygen species in HMEC induced by oxLDL; such intracellular antioxidative activity also decreased with decrement in HDL density from HDL3c (57% inhibition) to HDL2b (24%). The potent anti- apoptotic and antioxidative activities of the HDL3c subfraction were signiﬁcantly reduced (-18%, p<0.05, and -36%, p<0.05, respectively) in dyslipidemic subjects with Metabolic Syndrome (MetS; n=10) as compared to normolipidemic controls (n=5). Conclusions: Normolipidemic small dense HDL3 provide potent protection of human endothelial cells from oxLDL-induced apoptosis and from intracellular generation of ROS; these anti-apoptotic and antioxidative activities are attenuated in MetS. 1000-163 The Vasodilatory Action of Testosterone Is Independent of the Endothelium, Classic Androgen Receptor, Aromatase Activity, Nitric Oxide and Dilator Prostaglandins in Isolated Human Pulmonary Vessels Joanne Hall, Richard D. Jones, Stephanie Clarke, D. N. Hopkinson, G. J. Cooper, T. J. Locke, S. K. Survana, T. Hugh Jones, Kevin S. Channer, Division of Genomic Medicine, Shefﬁeld, United Kingdom Background: Testosterone (T) acts as a vasodilator and reduces myocardial ischemia in men with coronary heart disease. We determined whether T has a similar vasodilatory action in the human pulmonary circulation by characterising its mechanism of action. We examined the inﬂuence of the endothelium, androgen receptor, enzyme aromatase, nitric oxide and dilator prostaglandins in the dilatory response to T. Methods:The study was ethically approved, and full written informed consent was given by all patients. Pulmonary tissue was obtained from male (n=19, age = 64+2) and female (n=14, age = 58+6) patients undergoing lobectomies for lung carcinoma and was macroscopically normal. Pulmonary arteries (n=76) were loaded in a wire myograph and maintained at in vivo pressure (17.5mmHg) in oxygenated physiological saline solution (PSS) at 37° C. Vessels were left to equilibrate in fresh PSS plus one of the following pharmacologic agents for 30 min. 7µl ethanol vehicle (n=15); 10µM of the cyclooxygenase inhibitor indomethacin (I) (n=12); 100µM of the nitric-oxide synthase inhibitor L-NAME (L-N) (n=14); 10µM of the androgen receptor antagonist ﬂutamide (F) (n=12), 10µM of the aromatase inhibitor aminoglutethimide (amino) (n=12) and endothelial denudation (-endo) (n=12). A cumulative concentration response curve to U46619 (1-1000µM) was obtained and T (1-100µM) or equivalent concentrations of ethanol were then added cumulatively and changes in tension recorded. Results: There were no differences in dilatation to T and maximal dilatation to 100µM T was similar in vessels treated with each of the pharmacologic agents. Results are expressed as % maximal dilatation from baseline, corrected for the negligible vasopressor ethanol response, as mean ± SEM. Ethanol = -46.9± 3.8%, 10µM I = -45.6± 2.7%, 100µM L-N = -48.7± 9.4%, 10µM F = -41.0± 5.4%, 10µM amino = -53.1± 6.5% and -endo = -52.2± 6.7% dilatation respectively. All p>0.05 compared to E, analysed via Mann Whitney U Test. ACC_2006_8_VascularDisease.indd 344 1/4/06 5:21:20 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 345A Vascular D isease, H ypertension, and P revention Conclusions: This study demonstrates that T induces pulmonary dilatation via a mechanism that is independent of the endothelium, classic androgen receptor, the enzyme aromatase and the release of nitric oxide or dilator prostaglandins. 1000-164 High-dose Folic Acid Supplementation Improves Atherogenic Process in Predialysing Chronic Renal Failure Independent of Homocysteine-lowering Kam S. Woo, Ping Chook, Cheuk C. Szeto, Mu Qiao, Chi C. Kum, Lindy LT Chan, Chung P. Ho, Alex WY Yu, David S. Celermajer, The Chinese University of Hong Kong, Hong Kong, Hong Kong Background: Hyperhomocysteinemia is prevalent in chronic renal failure (CRF), which is associated with increased cardiovascular diseases, but the beneﬁt of homocysteine-lowering folic acid (FA) therapy has not been conﬁrmed in end stage CRF or coronary patients. Methods: 70 predialysing CRF patients were randomized to take 15mg FA or placebo daily for 12 weeks in double-blind cross-over fashion, followed by optional open label FA (15mg/ day) for 6 months. Flow-mediated dilation (FMD) of brachial artery and carotid intima-media thickness (IMT) (prognostic atherosclerotic markers) were measured by ultrasound. Results: Their mean age was 51.6±10.5 years, 50 (70%) were male, 8 (11.3%) were smokers, and mean cholesterol was 5.6±0.9mmol/l. After FA treatment, plasma folate signiﬁcantly increased but total plasma homocysteine (tHcy) decreased slightly (p<0.0001 in both). Brachial FMD and carotid IMT improved signiﬁcantly after FA but not after placebo. FMD improvement was independently related to changes in plasma folate (R=0.72, adjusted R2=0.48, p=0.005), but not changes in tHcy, blood pressure, lipids or glucose. Further improvement in FMD and IMT were sustained after open label FA despite deterioration of renal function. No adverse reactions were seen. Conclusion: High-dose FA supplementation improves arterial endothelial function and carotid IMT in predialysing CRF independent of homocysteine-lowering, supporting its application for atherosclerosis prevention in early CRF. Cross over Trial (n=70) Open Label (n=59) Baseline Placebo Folic Acid Baseline Folic Acid Creat (umol/l)) 190.3±69.9 195.6±81.5 209.6±124.2* 188.1±67.7 223.1±140.9** Folate (nmol/l) 41.1±30.0 39.6±21.7 162.3±26.0† 41.5±31.2 164.5±16.5† tHcy (umol/l) 16.9±5.2 17.0±5.7 14.5±4.5† 16.1±4.5 14.4±4.8† FMD (%) 5.5±1.6 5.5±1.5 6.8±1.6† 5.5±1.5 6.5±1.2† IMT (%) 0.78±0.21 0.77±0.21** 0.77±0.21† 0.78±0.23 0.76±0.22† Compared with placebo: *p<0.05, **p<0.01, †p<0.0001 1000-165 Effects of Mediterranean Diet or Supplements on Circulating Endothelial Progenitor Cells in Obesity Markus Porkert, Salman Sher, Elias Alexopoulos, Margaret F. Pedersen, Jennifer B. Terry, Kristen Narlow, Uma Reddy, Thomas R. Ziegler, Sandra B. Dunbar, Dean P. Jones, David Harrison, W. Robert Taylor, Diane Sutcliffe, Craig Hooper, R. Wayne Alexander, Arshed A. Quyyumi, Emory University, Atlanta, GA Background: Levels of circulating endothelial progenitor cells (EPC) are lower in patients with CAD, they can be stimulated by ischemia or vascular injury, and are considered to contribute to endogenous vascular repair. We hypothesized that dietary supplementation of mono-unsaturated and omega-3 fatty acids (O-3 FA) in obesity will improve oxidative stress and endothelial dysfunction, and this will modulate circulating EPC numbers. Methods: We studied 19 overweight non-smokers (BMI 27-40 kg/m2) without CAD, diabetes or statin therapy on a high saturated fat (>10%) diet. Subjects received either a Mediterranean-style diet for 1 month followed by 1 month of self-preparation (n=11), or supplements of ﬁsh oil (2.6 g EPA/DHA daily), walnuts (1/2 cup/day), and grape juice (16 oz/day) for 2 months (n=8). Measurements made at baseline, 4 weeks and 8 weeks included: fasting lipids; EPC counts (7-day culture assay of EPC colony forming units (CFU) from peripheral blood mononuclear cells); oxidative stress measured by the “determination of reactive oxygen metabolites” (d-ROMs) test that quantiﬁes organic hydroperoxides; and ﬂow mediated vasodilation (FMD) via brachial artery ultrasound. Results: Total cholesterol (186±7 vs 171±8mg/dl; p=0.003) and LDL (121±7 vs 105±7 mg/ dL; p=0.002) were reduced at 8 weeks. dROMS value was lower at 4 weeks (426±33 vs 377±28 Carr Units; p=0.03) with no further change at 8 weeks (390±22 Carr Units). FMD improved signiﬁcantly at 4 weeks (6.3%±0.8% vs 7.9%±0.9;p=0.04) and was maintained after 8 weeks (7.7%±1.3%). EPC counts were signiﬁcantly reduced compared to baseline after 4 and 8 weeks (from 95±9 to 58±9 and 48±8 CFU, respectively; p<0.006). All these changes were similar in the diet and supplement groups. Conclusions: Administration of the Mediterranean style diet or its major supplements to overweight adults decreases oxidative stress, and improves endothelial function. The simultaneous dramatic decrease in EPC counts suggests that obese subjects on a high- fat diet have basally stimulated circulating EPC levels. Thus, obesity and a high fat diet may place the vasculature under stress resulting in activation of endogenous reparative mechanisms. 1000-166 The Relation Between Aortic Distensibility and Calciﬁed Aortic Atherosclerosis: Cardiovascular MRI and CT Correlations Jie J. Cao, Vilmundur Gudnason, Johnny Pang, Jimmy Johannes, Gyda Karlsdottir, Sigurdur Sigurdson, W. Patricia Bandettini, Gudny Eiriksdottir, Lenore Launer, Tamara Harris, Andrew E. Arai, National Institutes of Health, Bethesda, MD, Icelandic Heart Association, Reykjavik, Iceland Background: Aortic distensibility decreases and calciﬁed atherosclerosis increases with aging and in patients with hypertension and coronary artery disease. We sought to test the hypothesis that aortic function is closely linked with atherosclerosis as evidenced by correlations between aortic distensibility and aortic calcium score. Methods: The study participants (n = 132) were randomly selected from the Age, Gene/ Environment Susceptibility Reykjavik Study, an observational epidemiology study of the elderly. Proximal aortic cross-sectional area was measured using steady state free precession cine MRI. Aortic distensibility was calculated as follows: {(maximum area - minimum area)/minimum area}/pulse pressure with blood pressure measured during the MRI scan. Aortic calcium was measured by CT and quantiﬁed as a modiﬁed Agaston score from regions of interest limited to the proximal descending area. Linear regression was used to correlate aortic distensibility with the logarithm of the aortic calcium score. Results: Of the 132 individuals 55% were female. The average age was 75.4±5.3 years. The mean aortic distensibility was 1.78±0.9x10-3 mm Hg-1, a value that is about one fourth of what is reported in the literature for young healthy controls. The median calcium score in the proximal descending aorta was 375 (inter-quartile range 101, 1054). Only 9 individuals (6.8%) did not have any detectable calcium. There was a signiﬁcant inverse correlation between aortic distensibility and calcium score (Pearson correlation coefﬁcient -0.431 (p<0.001)). In quartile analysis, aortic distensibility was 68% lower for subjects in the highest quartile of aortic calcium score relative to the lowest quartile. Aortic distensibility remained signiﬁcantly associated with calcium score after accounting for conventional risk factors including age, gender, history of hypertension, diabetes mellitus, smoking status and body mass index (p<0.001). Conclusions: Reduced aortic distensibility is associated with increased calcium deposition in the region. Our ﬁndings establish a direct link between reduced large artery function and increased burden of atherosclerosis. 1000-167 Antinanobacterial Antibody Titer Is an Independent Risk Factor for Coronary Artery Calciﬁcation Fatih Ertas, Taner Hasan, Ozay Akan, Cagdas Ozdol, Sevil Uysal, Cansin Tulunay, Tolga Kocum, Mustafa sahin, Huseyin Goksuluk, Neva Ciftcioglu, Katja Aho, E. Olavi Kajander, Cetin Erol, Ankara University School of Medicine, Ankara, Turkey, Nanobac Life Sciences, Tampa, FL Background: Calcium phosphate deposition (pathological calciﬁcation), is known to be present even in the early phases of the atherosclerotic plaque formation. Nanobacteria (NB) have emerged as a potential causative agent for pathologic calciﬁcation in human vasculature. In this study, we examined the relationship between the anti-NB antibody titers and the extent of coronary calciﬁcation. Methods: A total of 197 consecutive subjects undergoing multidetector computed tomography were enrolled into the study. The subjects having coronary artery calciﬁcation (n=103) were included in the coronary artery calciﬁcation (CAC) group, and those without calciﬁcation (n=94) were determined as controls. The commercially available ELISA kits (Nanobac) were used to detect IgG antibodies against NB in serum samples. Results: Mean titers of NB-antibodies were higher in individuals with CAC than with control group (0.4±0.4Units vs. 0.19±0.21 Units, p<.0001). Multivariate logistic regression analysis revealed that high anti-NB- titers were an independent correlate of CAC besides conventional risk factors such as age, hypertension, diabetes mellitus, and low HDL-C (Table). When the CAC scores were subcategorized: score 0, 1-100, 101-400, and >400, the CAC scores still correlated signiﬁcantly with the anti-NB antibody, especially in the group having CAC scores >400 ( p<.0001). Conclusions: Anti-NB antibodies are an independent risk factor for CAC and the antibody titers correlate with CAC scores. Table: Independent Correlates of Coronary Artery Calciﬁcation (CAC). Risk factors for CAC Multivariate p OR ( 95% CI) Age, years =0.008 1.05 (1.01 to 1.1) Systemic hypertension <.0001 5.8 (2.4 to 13.8) Diabetes mellitus 0.002 4.3 (1.1 to 16.3) High-density lipoprotein, (<40 mg/dL) <.0001 9 (3 to 27) Anti-NB antibody 0.004 8.7 (2 to 38) 1000-168 Measures of Arterial Stiffness and Wave Reﬂection Predict Walking Distance in Patients With Peripheral Arterial Disease LaPrincess Brewer, High-Seng Chai, Iftikhar J. Kullo, Mayo Clinic, Rochester, MN Background: Arterial stiffness is associated with decreased cardiorespiratory ﬁtness. We hypothesized that measures of arterial stiffness and wave reﬂection are predictors of the distance walked by patients with peripheral arterial disease (PAD). Methods: We studied 106 consecutive patients (mean age 69±10 years, 66% men) who underwent an exercise study after being referred for lower extremity arterial evaluation. Radial artery pulse waveforms were obtained by applanation tonometry (AtCor Medical, Sydney, Australia) and an ascending aortic pressure waveform derived by a validated transfer function. Aortic augmentation index (AIX) is the difference between the ﬁrst and second systolic peak of the ascending aortic pressure waveform indexed to the pulse pressure and T1R is the time to onset of the reﬂected wave. Ankle-brachial index (ABI) and walking distance were measured as per the laboratory protocol after excluding patients with non-compressible vessels and severe PAD (ABI<0.5). Survival analysis techniques were employed to identify predictors of walking distance from among age, sex, body mass index (BMI), mean arterial pressure, diabetes, smoking, ABI, and a measure of arterial stiffness (AIX, T1R, pulse pressure). Results: Diabetes was present in 19% of subjects and 80% were on hypertension medications. Mean (± SD) values were: AIX 31.2±10.9; T1R 134±17 msec; ABI 0.87±0.22; walking distance 188±82 yards. In both multivariable accelerated failure time and Cox proportional hazards models to predict walking distance, older age, female sex, greater BMI, lower ABI, and a measure of arterial stiffness (higher AIX, lower T1R, or higher pulse pressure) were associated with a lower walking distance. Higher AIX and lower T1R were associated with lower walking distance even after additional adjustment for pulse pressure. In analyses limited to patients with PAD (deﬁned as an ABI <1.0 at rest or post exercise, n = 89), higher AIX and lower T1R, but not ABI, ACC_2006_8_VascularDisease.indd 345 1/4/06 5:21:21 PM 346A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n were associated with lower walking distance. Conclusions: Measures of arterial stiffness are related to walking distance in patients with PAD. Arterial stiffness may be a target of therapy in patients with PAD. 1000-169 Gender Difference in the Impact of Multiple Cardiovascular Risk Factors on the Femoral Artery Intima-Media Thickness in Asymptomatic Young Adults: The Bogalusa Heart Study Timir Paul, Sathanur Srinivasan, Sharon Jackson, Paolo Raggi, Wei Chen, Gerald Berenson, Tulane University, New Orleans, LA, East Tennessee State University, Johnson City, TN Background: Males in general are considered to have more peripheral arterial disease (PAD) than females. Manifestations of PAD in relation to cardiovascular risk factors have been studied by ultrasound- assessed femoral artery intima-media thickness (IMT) mainly in middle - aged and older men and women. However, little is known on the impact of risk factors on the femoral IMT in young adults by gender. This study examined whether gender inﬂuences the impact of multiple cardiovascular risk factors on the femoral artery IMT in asymptomatic young adults in a biracial (black-white) population. Methods: Femoral IMT was measured by B-mode ultrasonography in 1080 males and females (aged 24- 43 years ; 71%white, 43% male) who participated in the Bogalusa Heart Study. Results: Age-adjusted femoral IMT showed a gender difference (males > females, p= 0.0001). In a bivariate analysis adjusted for age and race, IMT related signiﬁcantly to BMI, waist circumference, systolic and diastolic blood pressures, LDL cholesterol, HDL cholesterol (inverse relation), total to HDL cholesterol ratio and triglycerides in females and only to systolic blood pressure and LDL cholesterol in males. In a multivariate model age, systolic blood pressure, cigarette smoking and total to HDL cholesterol ratio related independently, in that order, to IMT in females; age and LDL cholesterol in males. In females, mean IMT increased with increasing number of risk factors deﬁned as values above the age- race- and gender- speciﬁc 75th percentile of systolic blood pressure, waist circumference, total to HDL cholesterol ratio and insulin along with positive smoking status (p for trend = 0.001), with respective mean IMT (mm) values of 0.61, 0.65, 0.72, and 0.77, for 0, 1-2, 3 and 4-5 risk factors. There was no such signiﬁcant trend in males. Conclusion: Although males vs females had thicker IMT, the observed increasing trend of femoral IMT with increasing number of risk factors in asymptomatic young female adults suggests that females are relatively more susceptible in this regard than males. These results suggest that gender should be considered in risk proﬁling and interventions. 1000-170 Quantitation and Distribution of Lipoprotein-Associated Phospholipase A2 and Oxidized Low Density Lipoprotein in Atherosclerotic Lesions of Carotid Endarterectomy Tissues Kasey C. Vickers, Colin Maguire, Robert Wolfert, William Insull, Jr., Paul Holvoet, Joel D. Morrisett, Baylor College of Medicine, Houston, TX, diaDexus, Inc., South San Francisco, CA Background: LpPLA2 has been implicated as a risk factor for cardiovascular disease. Ox- LDL, a substrate for LpPLA2, has long been considered a biomarker for atherosclerosis. Previous studies have reported the use of ELISA for the measurement of LpPLA2 and Ox- LDL in plasma. In the present study, we have extended the use of these assays to accurately and reproducibly measure these analytes in carotid endarterectomy (CEA) tissue extracts. In addition, we used labeled antibodies to co-localize these components in CEA tissues. Methods: Sixteen CEA tissues were digitally imaged and cut into 4 segments: common, bifurcation, internal, and external (n=64). Each segment was used for immunohistochemistry (IHC) and total protein extraction. LpPLA2 and Ox-LDL concentrations were determined by diaDexus PLACTM assay and Mercodia Ox-LDL ELISA. IHC was performed on 10µm frozen sections (mAb-LpPLA2 2C10, 4B4; mAb-Ox-LDL 4E6) and imaged with Delta Vision Spectris System. Results: In tissue extracts from common, bifurcation, internal and external segments the mean LpPLA2 levels (mass) were 106.93, 170.89, 213.8, and 94.4 ng/ug protein. The respective Ox-LDL levels were 2.38, 2.39, 2.89, 1.61 Units/ug protein. The levels of these two tissue components were signiﬁcantly correlated (r2=0.356, p<0.0001). Atherosclerosis, LpPLA2, and Ox-LDL were most abundant in the internal segments, and least abundant in the external segments (LpPLA2 p<0.025, Ox-LDL p<0.033). IHC (20X) revealed LpPLA2 and Ox-LDL to be localized in the highest concentrations to the shoulder region, lesion cap, and media interface. At 100X, the majority of LpPLA2 localized separately from Ox- LDL. LpPLA2 preferentially co-localized extracellularly with Ox-LDL aggregates over free standing Ox-LDL particles. This co-localization was also observed intracellularly in the cytosol of foam cells. Conclusions: Although the abundance of LpPLA2 and Ox-LDL in CEA tissues are signiﬁcantly correlated, the ratio between these two components is not ﬁxed. The high abundance and distribution patterns of LpPLA2 and Ox-LDL in atherosclerotic lesions suggest these two components reﬂect the lesion burden and may directly inﬂuence plasma concentrations. 1000-171 C-Reactive Protein and Plaque Composition in Patients with Stable Angina Pectoris (An Intravascular Ultrasound-Virtual Histology Study) Yoshiki Matsuo, Kubo Takashi, Akio Kuroi, Takashi Masho, Takashi Yamano, Masahiro Obana, Shigeho Takarada, Yasushi Hayashi, Toshio Imanishi, Yoshiaki Tomobuchi, Takashi Akasaka, Wakayama Medical University, Wakayama, Japan Background: Elevations of C-reactive protein (CRP) have been associated with vulnerable plaque formation. However, little is known whether elevated CRP is associated with the plaque composition in the patients with stable angina pectoris (SAP) whose plaque components are limited for the evaluation by gray-scale images of intravascular ultrasound (IVUS). The objective of this study is to assess the relationship between plasma CRP levels and coronary plaque composition using spectral analysis of IVUS radiofrequency data (IVUS-Virtural Histology™). Methods and Results: We performed IVUS examination in 42 patients with SAP who underwent percutaneous coronary intervention. Plaque composition of culprit lesion was investigated before intervention and spectral analysis of IVUS radiofrequency data was performed with IVUS-Virtural Histology™ software. Patients were divided into an elevated CRP group (≥0.3mg/dl) or a normal CRP group (<0.3mg/dl) according to plasma CRP levels. The volume of necrotic core in the elevated CRP group was signiﬁcantly larger than that in the normal CRP group (p<0.05). There was also a signiﬁcant positive correlation between plasma CRP levels and the amount of necrotic core (r=0.50, p<0.05). Conclusions: High levels of CRP were related to the volume of necrotic core obtained by IVUS-Virtural Histology imaging in patients with SAP. Our ﬁndings suggest that elevated CRP levels might reﬂect the inﬂammatory activity of coronary plaques even in SAP. 1000-172 Suppression of Osteoprotegerin as a Potential Mechanism of Healing After Coronary Intervention Prospero B. Gogo, Jr., David J. Schneider, Burton E. Sobel, Harold L. Dauerman, University of Vermont, Burlington, VT Background: Calciﬁed coronary plaques may be less prone to rupture and have less risk of subsequent ACS. Thus, culprit lesion calciﬁcation (CLC) may correlate with increased lesion stability as reﬂected by lower levels of inﬂammatory markers as well as the calciﬁcation regulator, osteoprotegerin (OPG). Methods: A prospective registry began in 2003. Blood from 99 patients undergoing PCI was obtained before and 24 hours after stenting. The levels of OPG, C-reactive protein, interleukin-6, and soluble CD40 ligand were determined by ELISA. CLC was evaluated by quantitative coronary angiography. Comparisons were stratiﬁed with respect to CLC with the use of non-parametric tests. Results: Patients with CLC (n=28) compared with no-CLC (n=71) were older, had lower creatinine clearance, and were nonsmokers (all p<0.02). Angiographic and procedural characteristics were similar between groups. CLC was associated with a reduced level of inﬂammation reﬂected by baseline sCD40L (4.65 vs. 7.15 pg/ml, p=0.05). High OPG correlated with diabetes, older age, and lower creatine clearance (all p<0.04). 24 hours after PCI, patients had less OPG and higher proinﬂammatory cytokines regardless of CLC status, particularly amongst patients with high baseline OPG. Conclusions: CLC is associated with lower levels of sCD40L consistent with increased plaque stability. The suppression of OPG after PCI may promote arterial calciﬁcation and be an integral part of the healing response to an acute inﬂammatory stimulus. POSTER SESSION 1001 Arterial Stiffness and Subclinical Atherosclerosis Tuesday, March 14, 2006, 8:30 a.m.-Noon Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 1001-173 The Heterogeneous Inﬂuence of Metabolic Risk Factors on Arterial Elasticity Sara Murray, John Nguyen, Daniel Duprez, Natalia Florea, Lynn Hoke, Jay Cohn, University of Minnesota, Minneapolis, MN Background: Early cardiovascular disease can be detected by abnormalities in large artery (LAE) and small artery elasticity (SAE). Metabolic risk factors contribute to changes in arterial elasticity, but it is unknown whether the effects are homogeneous across vessel size. The aim of this study was to examine the pattern of relation between metabolic risk factors and arterial compliance in a group of individuals with no prior cardiovascular disease. ACC_2006_8_VascularDisease.indd 346 1/4/06 5:21:21 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 347A Vascular D isease, H ypertension, and P revention Methods: The study enrolled 958 individuals without cardiovascular disease. LAE and SAE were determined by pulse wave registration at the radial artery using pulse contour analysis. Metabolic risk markers were obtained by serum measurements after an overnight fast. Multivariate linear regression was used to determine the effects of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, and glucose on LAE and SAE. Results are reported as coefﬁcients of the multivariate model for each variable of interest, along with the correlation coefﬁcient (r) and p-values. All models included the variable of interest, age, and gender. Results: An inverse association was seen between TC and both LAE and SAE. Every 50mg/ dL increase in TC was led to a mean 0.49mmHg x10 decrease in LAE (r=0.49, p=0.038). The same rise in TC predicted a mean 0.28mmHg x10 decrease in SAE (r=0.58, p=0.02). Triglycerides were also inversely related to LAE. A 50mg/dL increase in triglycerides led to a mean 0.19 mmHg x 10 decrease in LAE (r=0.49, p=0.011). By comparison, glucose was associated with only SAE. A 50mg/dL increase in glucose led to a 0.59mmHgx10 decrease in SAE (r=0.58, p=0.028). There was no association with HDL and LDL on either LAE or SAE. Also, TC/HDL and LDL/HDL ratios did affect arterial elasticity. Conclusion: This study found that higher cholesterol levels decreased both large and small artery elasticity. Higher triglyceride levels were only associated with reduced large artery elasticity. In comparison, higher glucose levels exerted an affect only on small arteries. These results imply that metabolic risk factors exert a differential effect on early vascular changes in healthy individuals. 1001-174 Gender Difference of Small and Large Artery Elasticity in Relation to Pulse Pressure Courtney O. Jordan, Daniel Duprez, Natalia Florea, Kathy Jones, Lynn Hoke, Jay N. Cohn, University of Minnesota, Minneapolis, MN Pulse pressure is considered either a risk factor or by others as a marker for preclinical cardiovascular disease. However, it provides only information of large artery stiffness and not of small artery disease. There is no information regarding gender difference of large artery elasticity (LAEI) and small artery elasticity (SAEI) in relation to pulse pressure. This study examined gender speciﬁc differences in arterial stiffness in a group of 958 asymptomatic subjects (384 women and 574 men, age range 19-85 years), who attended the Rasmussen Center for Cardiovascular Disease Prevention Center. Pulse pressure (PP) was calculated form systolic and diastolic blood pressure measurement in the sitting position. LAEI and SAEI were derived from radial artery pulse contour analysis. Results: Women Men P-Value n=384 n=574 PP (mmHg) 49.12 47.95 NS SD 16.72 14.76 LAEI (ml/mmHg x 10) 14.44 18.5 <0.0001 SD 5.12 5.75 SAEI (ml/mmHg x 100) 5.21 7.35 <0.0001 SD 2.83 3.24 Despite a similar pulse pressure in women vs men, large and small artery elasticity are signiﬁcantly lower in women vs men. LAEI and SAEI provide additional information about arterial stiffness than pulse pressure alone. There is an urgent need for gender speciﬁc reference levels for the estimation of large and small artery elasticity. 1001-175 Effects of Mental Stress on Brachial-Ankle Pulse Wave Velocity Fuminobu Ishikura, Toshihiko Asanuma, Shintaro Beppu, Osaka University Graduate School of Medicine, Suita, Japan Background: The brachial-ankle pulse wave velocity (baPWV), which had a good relationship with aging, blood pressure and hyperlipidemia, could be one of the good index of cardiovascular risk factors. The autonomic nerve system might inﬂuence the baPWV, because the autonomic nerve system regulates the vascular tonus, which also inﬂuences the baPWV. The purpose of this study is to evaluate the effect of mental stress on the baPWV. Methods: In 17 male patients with mood or anxiety disorders, the baPWV, mean systemic blood pressure (mSBP), heart rate (HR), ankle brachial pressure index (ABI), the score of Self-rating Depression Scale (SDS) and State-Trait Anxiety Inventory (STAI) were measured before and after medication; αβ blockers.such as carvedilol or arotinolol hydrochloride, and a selective serotonin reuptake inhibitor (SSRI), such as ﬂuvoxamine or paroxetine. Results: After those treatments, symptoms of patients signiﬁcantly improved. The score of SDS and STAI signiﬁcantly improved (SDS: 47±11 vs. 37±9, STAI: 50±14 vs. 39±12, p < 0.01), and mSBP and HR slightly but not signiﬁcantly decreased (mSBP: 95±11 vs. 92±11mmHg, HR: 67±12 vs. 61±10). The baPWV signiﬁcantly decreased from 1462±306 to 1351±223cm/s, but the ABI did not change. The baPWV had a rough correlation between age and mSBP. The right ABI and baPWV did not differ from the left one. Conclusions: The baPWV signiﬁcantly improved concomitant with the improvement of mental stress in patients with mood or anxiety disorders after medical treatments, such as αβ blockers and SSRIs, without the signiﬁcant change of mSBP and HR. The αβ blockers and SSRIs could improve the autonomic nerve system, which also improves the vascular stiffness. Mental stress is one of the important factor to inﬂuence the baPWV and we should pay attention mental condition to measure the baPWV. 1001-176 Angiotensin Converting Enzyme Inhibition Reduces Aortic Stiffness in Stable Coronary Artery Disease. Results of the Peace Hemodynamic Study Gary F. Mitchell, Mark E. Dunlap, Wayne Warnica, Anique Ducharme, J. Malcolm O. Arnold, Scott D. Solomon, Michael J. Domanski, Kathleen A. Jablonski, Madeline M. Rice, Marc A. Pfeffer, for the PEACE Investigators, Cardiovascular Engineering, Inc., Waltham, MA, Brigham and Women’s Hospital, Boston, MA The Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial evaluated ACE inhibition with trandolapril as compared with placebo added to conventional therapy in patients with stable coronary disease and normal or near normal LV function and found no difference in the primary endpoint of death from cardiovascular causes, myocardial infarction or coronary revascularization. The PEACE hemodynamic study evaluated pulsatile hemodynamics a median of 52 months after randomization in a subset of 300 participants from 6 centers. Carotid-femoral pulse wave velocity (CFPWV), a measure of aortic stiffness, was assessed from tonometry of the carotid and femoral arteries and body surface transit distances. Patients randomized to trandolapril, compared with placebo, tended to be older (64.2±7.9 vs. 62.9±7.7 years, P=0.14), with a higher BMI (28.5±4.0 vs. 27.8±3.9 kg/m2, P=0.09) and lower ejection fraction (57.1±8.1 vs. 58.7±8.4%, P<0.01). At the time of the hemodynamic study, the trandolapril group had lower mean arterial pressure (MAP, 93.1±10.2 vs. 96.3±11.3 mm Hg, P<0.01). In an analysis that adjusted for baseline characteristics and follow-up quintile of MAP, patients randomized to trandolapril had lower CFPWV as compared with placebo (Figure, P<0.01). We conclude that ACE inhibition with trandolapril produced a modest reduction in aortic stiffness beyond what would be expected from blood pressure lowering or differences in baseline characteristics alone. 1001-177 Procollagen Type III Amino-terminal Peptide (PIIINP) and Surrogates of Ventricular/Vascular Stiffness in Chronic Kidney Disease Santo Dellegrottaglie, Valerie Cattan, Faiez Zannad, Xiaotong Zhang, Soyoung Chang, Brenda Gillespie, Frederic Finkelstein, Margaret Kiser, George Eisele, Alan L. Hinderliter, Nathan W. Levin, Sanjay Rajagopalan, Rajiv Saran, Zena and Michael A.Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY, University of Michigan, Ann Arbor, MI Background: Chronic kidney disease (CKD) is associated with alterations in cardiovascular compliance. Procollagen type III amino-terminal peptide(PIIINP) is a circulating marker of collagen degradation that has been found to be elevated in conditions associated with extra-cellular matrix turnover. Accordingly, the aim of the present study was to characterize the relationship of PIIINP with GFR and surrogates of vascular and ventricular stiffness. Methods: The study included 244 patients (mean age 59±15 years; 53% males) from the Renal Research Institute-CKD Study [mean glomerular ﬁltration rate (GFR)=25±11 mL/min/1.73m2)]. 78% of patients were in stage 4-5 (GFR<30 mL/min/1.73m2), 31% were diabetics and 20% with previous diagnosis of coronary artery disease. PIIINP was analysed by radioimmunoassay (normal reference < 4.2 µg/L). 2D and echocardiography was used to assess LV mass index (g/m2) and transmitral LV ﬁlling pattern (absent, mild, moderate or severe diastolic dysfunction based on E/A ratio). Arterial stiffness was determined by measuring pulse wave velocity (PWV, m/sec) from carotid and femoral pressure wave contours. Results: Overall, high mean values of PIIINP were obtained (8.9±7.8 µg/L, range 0.4- 83.7 µg/L). PIIINP increased with worsening renal function: 7.2±4.6 µg/L (CKD stage 3) vs. 8.7±6.4 µg/L (CKD stage 4) vs. 15.4±18.1 µg/L (CKD stage 5; p<0.0001 for the trend). PIIINP correlated with GFR (p=0.002) and PWV (p=0.03) but not with LV mass index or E/A ratio. A multivariate analysis controlling for age, sex, race, diabetes, diagnosis of coronary artery disease, diagnosis of congestive heart failure and GFR as covariates showed that PWV (p=0.019) correlates signiﬁcantly with PIIINP. GFR, caucasian race and diabetes remained as signiﬁcant predictors for PIIINP in multivariate analysis, while LV mass index and E/A ratio do not signiﬁcantly predict PIIINP. Conclusion: PIIINP is increased in CKD and correlates with the extent of renal impairment. PIIINP is associated with markers of increased arterial stiffness but not with LVH and diastolic dysfunction. These ﬁndings support further evaluation of PIIINP as a marker of cardiovascular ﬁbrosis in CKD. ACC_2006_8_VascularDisease.indd 347 1/4/06 5:21:22 PM 348A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n 1001-178 High Levels of Subclinical Atherosclerosis in Rural South Asian Indians Could be Explained by Impaired Protection by HDL Clara K. Chow, Brendan McQuillan, Krishnam Raju, Rama Raju, Bruce Neal, David Celermajer, The George Institute for International Health, Sydney, Australia, Royal Prince Alfred Hospital, Sydney, Australia Background: South Asian Indians have high levels of cardiovascular disease despite generally lower levels of conventional risk factors. This may reﬂect a greater susceptibility to known risk factors or exposure to novel risk factors. We evaluated risk factor levels and subclinical atherosclerosis (assessed by common carotid intima-media thickness [IMT]) among rural Indians to determine the extent to which vascular disease is explained by conventional risk factors in each group. Methods: Cardiovascular risk factors and ultrasound-assessed carotid IMT measured in randomly selected adults from two villages in rural Andhra Pradesh, India (n=303) were compared to those from an urban Caucasian population from Australia (n=1111). Crude and multivariable adjusted comparisons of mean population levels of carotid IMT were made using linear regression models. Differences between populations in the associations of individual risk factors with carotid IMT were compared using linear regression models including population interaction terms. Results: Urban Australians had generally worse levels of conventional risk factors (blood pressure, total cholesterol, LDL cholesterol, BMI, diabetes) compared with rural Indians except for smoking and HDL. However age and sex adjusted mean carotid IMT was higher in rural Indians (0.74mm, 95% conﬁdence interval 0.73-0.76) compared to urban Australians (0.69mm, 0.69-0.70;p<0.001). After adjustment for risk factors, these differences remained signiﬁcant. Between populations the associations of risk factors with carotid IMT were not signiﬁcantly different for increasing systolic BP, LDL, glucose, BMI, waist circumference and current smoking. Increasing levels of HDL-cholesterol, however, were associated with increasing carotid IMT (β = 0.21, p<0.001) in rural Indians as compared to decreasing carotid IMT (β = -0.05, p<0.001) in urban Australians (p value for difference between populations p<0.001). Conclusions: Higher levels of subclinical atherosclerosis in rural Indians as compared to urban Australians may be a consequence of different effects of HDL in the two populations and warrants further examination. 1001-179 Endothelial Dysfunction and Increased Carotid Intima-Media Thickness in Primary Antiphospholipid Syndrome Marietta Charakida, Julian P. Halcox, Shirish Sangle, David D’Cruz, Ann E. Donald, Charles G. Mackworth-Young, Nigel J. Klein, Graham Hughes, John E. Deanﬁeld, Vascular Physiology Unit, London, United Kingdom, The Rayne Institute, St Thomas’ Hospital, London, United Kingdom Background: Antiphospholipid syndrome (APS) is characterised by increased thrombogenicity and/or pregnancy morbidity in the presence of raised levels of antiphospholipid antibodies (aPL). Recent data associate aPL with endothelial activation, enhanced oxidative stress and decreased plasma nitric oxide. It remains unclear whether patients with APS are at increased risk of developing premature atherosclerotic disease. Methods: We studied 90 patients with primary APS aged 45.9±1.08 yrs (mean±SE) and a control group of 90 people aged 46.5±1.19 yrs without positive aPL matched for sex and cardiovascular risk factor proﬁle. High resolution ultrasound was used to determine carotid intima-media thickness (cIMT), endothelium dependent ﬂow mediated dilatation (FMD) and endothelium independent nitroglycerine mediated dilatation (NTG) of the brachial artery. Results: APS patients had signiﬁcantly increased cIMT compared to controls (0.75±0.02mm vs 0.64±0.01mm, p<0.001). FMD was reduced in APS (6.1±0.4% vs 9.4±0.5%, p<0.001). NTG responses were similar in APS and controls. Multivariate analysis (adjusting for cardiovascular risk factors including high sensitivity C-reactive protein and body mass index) revealed that age (�= 0.37, p<0.001), systolic blood pressure (�=0.17, p=0.02), FMD (�=-0.20, p<0.01) and APS (�=0.27, p<0.001) were the only independent predictors for cIMT, whereas APS (�=-0.34, p<0.001), age (�=-0.16, p=0.03) and baseline diameter (�=-0.39, p<0.001) were the only independent determinants of FMD. Conclusions: APS is associated with endothelial dysfunction and increased carotid intimal thickening. Further prospective studies are required to evaluate the impact of these arterial wall abnormalities on cardiovascular risk stratiﬁcation in this condition. POSTER SESSION 1002 Peripheral Arterial Disease Treatment Tuesday, March 14, 2006, 8:30 a.m.-Noon Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 1002-180 Outcomes After Endovascular Therapy for Lesions Classiﬁed According to the Transatlantic Intersociety Consensus (TASC) Document Lou Vadlamani, William A. Gray, Chin Kim, Khusrow Niazi, CArdiovascular Medicine, Atlanta, GA, Crawford Long Hospital, Atlanta, GA Objective: To evaluate short and long-term therapeutic success rates in Iliac (IA) and Superﬁcial Femoral artery (SFA) lesions as classiﬁed according to the TASC document, using an endovascular approach. Methods: 473 peripheral arteriograms were reviewed in a retrospective fashion and lesions were classiﬁed using TASC criteria. Immediate therapeutic success was deﬁned as (i) successful intra-luminal placement of a wire distal to the lesion and (ii) a < 20 % visually estimated residual stenosis at the conclusion of the procedure. Patients were then followed using non-invasive studies at 6 month intervals. Procedural complications including: (i) access site bleeding requiring increased hospitalization (ii) vessel complications requiring surgery (distal embolization, dissection, perforation). Results: There were a total of 205 IA lesions, of which 57 (27%) were TASC A, 66 (32%) TASC B, 49 (24%) TASC C, and 33 (22%) TASC D. Success rates were 100 % with these lesions and the complication rate was 4 % (8 access site bleeds). Restenosis rates at 6 and 12 months were: TASC A - 9 and 12 %; TASC B - 8 and 13%; TASC C - 13 and 17 %; TASC D - 16 and 21 % respectively. Of 268 SFA lesions, 249 (93%) were successfully treated. Of these, 54 (21%) were TASC A, 89 (36%) TASC B, 93 (37%) TASC C, and 13 (6%)TASC D. There were 18 (7.2%) complications. Restenosis rates at 6 and 12 months were: TASC A - 11 and 16%; TASC B - 14 and 19 %; TASC C - 18 and 21 %; TASC D - 23 and 31 % respectively. Conclusions: Our results demonstrate excellent immediate success independent of TASC classiﬁcation using an endovascular approach to lesions in the IA and SFA. However, TASC C and D lesions in both distributions appear to have less durable results with higher restenosis rates than the TASC A and B lesions. 1002-181 Femoral Pseudoaneurysms: Management with Percutaneous Thrombin Injections Ilona Hofmann, Albrecht Römer, Thomas Middeldorf, Horst Sievert, for the members of The German Multicenter ThrombinRegistry, CardioVascular Center, Frankfurt, Germany, Sankt Katharina Hospital, Frankfurt, Germany Background:False aneurysms develop at the puncture site in up to 8 % of catheter procedures. This can be treated surgically or by ultrasound controlled manual compression. Another method is to inject thrombin into the aneurysm under ultrasound guidance. We evaluated safety and efﬁcacy in a multicenter registry. Methods: in 592 consecutive patients (age: 31-94years, median 70) a pseudoaneurysm (590 femoral arteries, 2 brachial arteries) was diagnosed 0 to 250 days (median 2 days) after a catheter procedure. The diameter of the aneurysm ranged from 0, 1 x 0, 5 x 0, 5 (L x W x D) to 8x11x16 cm (median 2 x 2 x1, 6 cm). 20 U to 4000 U. of thrombin solution (median 400 U) were injected into the aneurysm under ultrasound guidance. Results: The procedure was technically successful after the ﬁrst injection in 533 Patients (90 %), after a second injection in additional 38 patients (7%) and after a third injection in additional 8 patients (1%). This overall acute success rate was 583/592 (98%) In 4 (0, 7%) additional patients the injection initially resulted in a partial occlusion of the aneurysm followed by a spontaneous complete seal within 24 hrs to 7 days after the procedure. In 7 patients surgery was performed after successful closure of the aneurysm in order to remove the resulting haematoma. 9 (1, 5%) other patients underwent surgery because the thrombin injection failed. Complications: temporary thrombus formation (n=2) without further consequences, transient paresthesia in the leg during injection (n=3), deep venous thrombosis (n=3). Conclusions: Ultrasound guided Thrombin injection is a safe, painless, effective and rapid alternative to treat false aneurysms. Complications and recurrent pseudoaneurysms are very rare. It has become the treatment of choice in our institution and should be the initial treatment of choice for patients with post-catheterization pseudoaneurysms. 1002-182 The Efﬁcacy and Safety of EECP in Patients with Peripheral Arterial Disease Bhavik V. Thakkar, Alan T. Hirsch, Bradley A. Bart, Greg Barsness, Lisa Kennard, Sheryl F. Kelsey, Timothy D. Henry, Minneapolis Heart Institute Foundation, Minneapolis, MN Background: Enhanced external counterpulsation (EECP) therapy decreases angina and improves quality of life in patients with coronary artery disease and refractory angina. Peripheral arterial disease (PAD) is considered a contraindication to EECP therapy, but there is no data regarding the safety and efﬁcacy of EECP in this common clinical scenario. Methods: The International EECP Patient Registry (IEPR) phase 2 collected data from patients receiving EECP from January 2002 through October 2004, including a history of PAD. We compared baseline cardiovascular disease, changes in anginal class and quality of life (Duke Activity Score Index (DASI) score) in patients with and without PAD. Results: 23% of patients in IEPR-2 had PAD. These patients were older, had more extensive CAD, lower LVEF, more severe angina at baseline as well as higher risk factors and comorbidities (see table). Conclusions: Higher event rates during EECP likely reﬂect the burden of atherosclerotic disease. Despite the complexity of disease, individuals with PAD enjoy comparable improvements in angina and quality of life in response to EECP. Baseline demographics Patients without PAD n=2111 Patients with PAD n=646 p-value Adverse events during therapy Patients without PAD n=2111 Patients with PAD n=646 p-value Age (yrs) 66.5 69.4 <0.001 Hospitalization 11.2 15.4 <0.05 CHF (%) 25.0 36.4 <0.001 Unstable angina 3.4 6.3 <0.01 LVEF <35% 17.7 22.6 <0.01 CHF 1.4 3.4 <0.01 Cerebrovascular disease (%) 21.8 37.9 <0.001 Death/MI/CABG/ PCI 2.6 4.8 <0.01 Chronic renal insufﬁency (%) 8.5 21.3 <0.001 Efﬁcacy Class IV angina 24.4 35.5 <0.001 Angina status decreasing ≥1 class 76.8 75.0 NS Hx of hypertension 79.0 86.4 <0.01 DASI score % improved 64.1 60.3 NS Hx of diabetes 39.9 57.2 <0.001 Hx of tobacco use 56.6 64.9 <0.001 ACC_2006_8_VascularDisease.indd 348 1/4/06 5:21:23 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 349A Vascular D isease, H ypertension, and P revention 1002-183 Effects of Percutaneous Transluminal Angioplasty (PTA) and Endovascular Brachytherapy(EVBT) on Vascular Remodeling of Human Femoropopliteal Artery: 2-Years Follow-Up by Noninvasive MR Plaque Imaging Augusto Gallino, Rolf Wyttenbach, Mario Alerci, Felix Mahler, Mario Di Valentino, Juan J Badimon, Valentin Fuster, Roberto Corti, University Hospital Zurich, Zurich, Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland Background: Percutaneous transluminal angioplasty (PTA) of severely stenotic peripheral vascular lesions is hampered by higher restenosis rate. The effects of PTA on vascular wall as well of the anti-restenotic properties of endovascular brachytherapy (EVBT) remain unclear. Magnetic resonance imaging (MRI) allows in vivo noninvasive assessment of the vascular effects of such treatment strategies. We aimed to elucidate the vascular effect of PTA and PTA+EVBT by serial MRI. Methods: Twenty symptomatic patients with severe stenosis of the femoropopliteal artery were randomly assigned to PTA (n=10) or PTA+EVBT (n=10, 14 Gy by g-source) and imaged by high-resolution MRI before, and 24-hours, 3-months and 2 years after intervention. An independent observer blinded to the procedure analyzed the MRI data. Results: At 24-hours, cross-sectional MRI revealed that lumen area (+86% and +67%) and total vessel area (+47% and +34%) similarly increased in the PTA and PTA+EVBT group. All patients showed severe splitting of the atherosclerotic plaque, resulting in an irregularly shaped lumen. At 3-months, MRI revealed a signiﬁcant difference in lumen area change between the PTA and PTA+EVBT group (+40% and +106%, respectively; p=0.026) and in the total vessel area (+14% and +39%, respectively; p=0.018), which was maintained at 2 years follow-up. PTA induced plaque disruption persisted at 3 months in 50% and at 2 years in 10% in PTA+EVBT patients only. Conclusions: After PTA, there is deep disruption of the atherosclerotic plaques and extensive remodeling process of the arterial wall. Luminal loss after PTA is partially due to inward vessel remodeling. Brachytherapy avoid inward remodeling and induces an increase in lumen area, but partially prevent healing of disrupted vessel surface. 1002-184 Percutaneous Transluminal Angioplasty of the Subclavian Arteries Michel Henry, Isabelle Henry, Antonios Polydorou, Amanda Polydorou, Michèle Hugel, Michel Henry MD, Cabinet de Cardiologie, Nancy, France Purpose: To review feasibility, safety and long-term results of sub-clavian artery angioplasty. Methods: Over 14 years, 237 patients (males: 135, mean age: 64±12y) underwent percutaneous treatment for sub-clavian artery occlusive disease. Indications for treatment were upper limb ischemia (n=125) , vertebrobasilar insufﬁciency (n=128), coronary steal (n=11) and anticipated coronary bypass surgery in asymptomatic patients (n=26). 192 arteries were stenosed and 45 occluded. Mean % stenosis was 81.9±7.6, mean lesion length was 23.8±8.8 mm. Percutaneous techniques included retrograde femoral (n=163), brachial artery (n=47) access or both (n=14), and in 4 cases, the “pull through technique”. An isolated balloon angioplasty was performed in 59 cases. We implanted 132 balloon expandable stents, 32 self-expandable stents. Results: Technical success was obtained in 223 lesions (94%). Only 31 occlusions were recanalized (69%). Four periprocedural events occurred (1.2%), 1 major (fatal) stroke, 1 T.I.A., 2 arterial thromboses. At follow-up (mean follow-up: 65.8 months ± 33.5), we had 27 restenoses (12%). 13 occurred following angioplasty alone (18.8%) and 14 following angioplasty and stent implantation (8.4%) . Primary (PI) and secondary (PII) patencies on an intention to treat basis at 10 year follow-up were 78.1% and 84.5% respectively. In patients without initial stent placement, the rates were 67.5% and 75.5% while in those with stents, the rates rose to 89.7% and 96.9% (P<0.01). PI for all recanalized lesions were 84.6%, 79.1% without stent, 89.7% with stent (P<0.04) and PII 91.6%, 88.5%, 96.9% respectively (P<0.02). Conclusion: P.T.A. is currently the treatment of choice for subclavian artery lesions. It is a safe and effective procedure associated with low risks and good long-term results. Stents seem to limit the restenosis rate and improve long-term results. POSTER SESSION 1003 CRP, HDL, NO and CVD Tuesday, March 14, 2006, 8:30 a.m.-Noon Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 1003-185 Withdrawal Effect After 4-Year Statin Therapy on C- reactive Protein Is Independent of LDL-cholesterol Change Pim van der Harst, Folkert W. Asselbergs, Hans L. Hillege, Stephan J. Bakker, Adriaan A. Voors, Dirk J. van Veldhuisen, Wiek H. van Gilst, PREVEND-IT Investigators, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Background In addition to lowering cholesterol, statins effectively lower levels of C- reactive protein (CRP). The effects of withdrawal from long-term statin therapy on C- reactive protein (CRP) are unknown. Methods We evaluated the effects of withdrawal of pravastatin (40mg) treatment on CRP levels in 586 subjects participating in the randomized, placebo controlled PREVEND-IT study. We measured CRP levels at baseline, after 4 years of randomized treatment, and 3 months after discontinuing study treatment. Results Median CRP levels before randomization to study treatment were 1.3 mg/L for both groups and baseline LDL cholesterol was 154 mg/dL in placebo and 159 mg/ dL in pravastatin allocated patients (P=NS). Four years after randomization, placebo treated patients had a non-signiﬁcant 4.3 percent increase of CRP levels (P=0.4), in contrast to pravastatin treated patients who had a 16 percent decrease (P=0.002). LDL cholesterol changed only in pravastatin treated patients (-27% to 115 mg/dL, P<0.001). Withdrawal of pravastatin lead to a signiﬁcant increase in both CRP and LDL cholesterol levels to approximately pre-treatment levels (to 1.4 mg/L; P=0.024, and 153 mg/dL; P<0.001, respectively). However, the relative and absolute change of CRP by withdrawal of pravastatin did not correlate with change in LDL cholesterol. The difference between pravastatin and placebo groups in terms of change in CRP by withdrawal was consistent in analysis stratiﬁed by gender, age, bodymass index, smoking status, blood pressure, and baseline levels of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. Conclusions Withdrawal of pravastatin treatment resulted in rapid and signiﬁcant increase in CRP levels. These data provide mechanistic support for the acute increase in cardiovascular risk associated with statin discontinuation. The cause of CRP increase after discontinuation appears to be unrelated to increase in LDL and remains to be elucidated. 1003-186 Lipid Effects of Torcetrapib With and Without Atorvastatin Are Optimized by Morning Dosing: Results From Pharmacokinetic/Pharmacodynamic Analyses Megan Gibbs, Matthew Riggs, Tanya Russell, Greg Wei, Andres Digenio, Tom Thuren, Charles Shear, Pﬁzer Global Research and Development, Groton/New London, CT Background: Torcetrapib (T), a potent inhibitor of cholesteryl ester transfer protein (CETP), raises HDL-C and decreases LDL-C. The LDL-C lowering effect of T is enhanced by the addition of the HMG-CoA reductase inhibitor, atorvastatin (A). Both HMG-CoA reductase and CETP show diurnal variations in activity, with HMG-CoA reductase being highest in the evening (PM), and CETP activity being highest in the morning (AM). Although evening dosing is recommended for most other statins, the pharmacokinetic/ pharmacodynamic (PK/PD) proﬁle of A allows for both AM and PM dosing. The purpose of two phase 1 studies was to investigate the PK and lipid effects of AM versus PM dosing of T alone and the T/A combination. Methods: The T only trial was a double-blind study, with subjects randomized into AM or PM treatment with either placebo or T 100 mg. The T/A study was an open-label study, with healthy adult subjects randomized to receive either AM or PM treatment with either placebo or T/A 60 mg/20 mg for 14 days. Primary PK endpoints were Cmax and AUC for both T and A. Results: In the T only study, Cmax and AUC were 30% and 25% lower after PM versus AM dosing. LDL-C levels decreased from baseline by 4.8% and 7.9% after AM and PM dosing, respectively. HDL-C levels followed PK results and increased by 32.5% and 21.1% after AM and PM dosing, respectively, with a statistically signiﬁcant difference between treatment groups of -11.4% (95% CI; -21.4, -1.4). In the T/A study, Cmax and AUC for T were 17% and 32% lower after PM relative to AM dosing, but were almost identical for A, with PM to AM ratios of 103.3% and 99.5% for Cmax and AUC, respectively. For T/A treatment, the percentage increase from baseline in HDL-C differed by -12.1% (95% CI; -26.0, 1.8) and the percentage decrease in LDL-C differed by 2.1% (95% CI; -4.6, 8.8) after PM compared with AM dosing. Conclusions: Morning dosing of T appears to provide maximal beneﬁt on HDL-C. Dosing ﬂexibility of A makes it an appropriate choice for development of combination T/A and allows AM dosing of T/A in order to maximize therapeutic beneﬁt on HDL-C and LDL-C. Phase III studies of T/A dosed in the AM are ongoing. 1003-187 Lipid-Lowering Results From the First Large-Scale Trial of Statin Therapy in Hispanic-American Patients With Hypercholesterolemia: STARSHIP Ramon Lloret, Steven Haffner, Joseph Ycas, Michael Stein, STARSHIP Study Group, Cardiovascular Center of South Florida, Miami, FL, AstraZeneca, Wilmington, DE Background The US Hispanic population has grown to 40 million persons but remains underdiagnosed, undertreated, and underrepresented in most clinical trials. The STudy Assessing RosuvaStatin in HIspanic Population (STARSHIP) (4522US/0007) was the ﬁrst prospective, randomized, controlled trial comparing lipid-lowering therapy in Hispanic Americans. Methods After 6-wk dietary lead-in, 696 patients (50% male) with hypercholesterolemia and moderate to high risk of CHD event were randomized to 1 of 4 open-label treatments for 6 wks: rosuvastatin (RSV) 10 or 20 mg or atorvastatin (ATV) 10 or 20 mg. Results Mean age of patients was 58 yrs, with CHD or CHD risk equivalents in 59%; 44% had diabetes; mean BMI was 30.0 kg/m2. RSV reduced lipids better than ATV (Table). On RSV 10 mg, 78% of patients overall reached NCEP ATP III LDL-C targets; 9 out of 10 high-risk patients on RSV 20 mg reached target. All 4 treatments were well tolerated; 92% of patients completed the trial. One patient on ATV 20 mg had liver function tests >3x ULN on 2 consecutive measurements. Change in dipstick proteinuria from none/trace at baseline to >++ at wk 6 was observed in 5 patients on RSV and 1 on ATV. No patient had doubling of serum creatinine. No cases of myopathy or CK >10x ULN occurred. Conclusion After 6 wks of therapy in hypercholesterolemic Hispanic patients, RSV 10 and 20 mg had signiﬁcantly greater efﬁcacy than milligram-equivalent doses of ATV in reducing LDL-C, non-HDL-C, and TC. Overall safety experience was similar for both statins. ACC_2006_8_VascularDisease.indd 349 1/4/06 5:21:23 PM 350A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n Rosuvastatin 10 mg (n=172) Rosuvastatin 20 mg (n=167) Atorvastatin 10 mg (n=160) Atorvastatin 20 mg (n=161) LDL-C (% change) -45.2 * -50.0 † -35.9 -42.4 Non-HDL-C (% change) -40.9 * -44.6 † -32.6 -39.2 Total cholesterol (% change) -32.4 * -34.9 † -25.6 -30.9 HDL-C (% change) +5.5 +5.7 +3.5 +4.3 Triglycerides (% change) -20.1 -17.7 -13.9 -22.3 Met NCEP ATP III LDL-C goal All risk groups 78% 88% 60% 73% Met NCEP ATP III LDL-C goal High-risk group (<100 mg/dL) 74% (n=116) 91% (n=106) 52% (n=106) 62% (n=106) *p<0.017 vs atorvastatin 10 mg, NS vs atorvastatin 20 mg; † p<0.017 vs atorvastatin 20 mg Analysis of variance with Bonferroni adjustment for multiple comparisons to a signiﬁcance level of 0.017. Summary statistics only were calculated for NCEP ATP III data. ATP = Adult Treatment Panel; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; NCEP = National Cholesterol Education Program; non-HDL-C = high-density lipoprotein cholesterol 1003-188 Lower Plasma High-Density Lipoprotein Remains an Important Independent Predictor of Death or Non-Fatal Myocardial Infarction Among Statin Treated Patients Following Cardiac Catheterisation Nick Newall, Roger Moore, Paul Browning, Rodney H. Stables, Mark Jackson, Cheng Hock Toh, Alan Shenkin, David Ramsdale, The Cardiothoracic Centre, Liverpool, United Kingdom, The Royal Liverpool and Broadgreen University Hospital, Liverpool Background: Low-density lipoprotein (LDL) lowering with statin therapy has been shown to reduce major cardiovascular adverse events. The relationship between LDL level on treatment and adverse outcomes is less certain. We sought to compare the prognostic utility of fasting lipid screening among contemporary patients with high statin use undergoing diagnostic cardiac catheterisation. Method: We conducted a prospective cohort study of 2444 individuals undergoing cardiac catheterisation for all indications. Patients had fasting blood samples drawn pre-procedure, clinical and angiographic data were recorded in a validated electronic database and patients followed for death or non-fatal myocardial infarction (MI) over one year. Outcomes were compared with lipid, clinical and angiographic variables using Cox proportional hazard tests. Results: There were 98 (4.3%) deaths or MI pre-revascularisation among 2297 (94.0%) patients with complete data. At enrolment 69.1% were on statin therapy. Cox multivariate forward conditional analysis identiﬁed lower plasma HDL but not higher triglyerides, or LDL as an independent predictor of death or MI in the year following cardiac catheterisation (see table). Conclusion: Low plasma HDL is prognostically more important than on treatment LDL, or triglyceride levels among patients undergoing cardiac catheterisation. Low HDL is a modiﬁable risk factor and should be sought and corrected in patients undergoing cardiac catheterisation. Independent predictors of death or MI Hazard Ratio (HR) 95% Conﬁdence interval lower 95% Conﬁdence interval Upper Signiﬁcance (p) Left Ventricular Ejection Fraction 0.978 0.964 0.993 0.003 Peripheral Arterial disease 2.847 1.615 5.020 <0.001 Unstable Symptoms 2.507 1.622 3.877 <0.001 Aortic Stenosis 3.349 1.828 6.136 <0.001 Number of Coronary Vessels with >75% stenosis 1.241 1.004 1.535 0.046 Age (years) 1.045 1.021 1.070 <0.001 Plasma HDL mmol/l 0.460 0.236 0.897 0.023 1003-189 Atorvastatin but Not Vitamin C, Affects Endothelial Function, Asymmetric-Dimethyl-Arginine Levels and Inﬂammatory Process, in Patients With Diabetes Mellitus Type 2, and Low Cholesterol Level Dimitris Tousoulis, Charalambos Antoniades, Pantelis Kourtelaris, Carmen Vasiliadou, Costas Toutouzas, Costas Tsiouﬁs, Stella Brilli, Costas Tentolouris, Gerasimos Siasos, Christodoulos Stefanadis, Athens University, Athens, Greece Background: Endothelial dysfunction in diabetes mellitus (DM) is associated with increased oxidative stress, enhanced proinﬂammatory cytokines expression and increased levels of endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). We evaluated the effect of atorvastatin and vitamin C, on endothelial function, inﬂammatory process and ADMA levels, in patients with DM. Methods: Forty-one patients with DM and low cholesterol level were randomized to receive atorvastatin 10mg/day (ATR, n=15), vitamin C 2g/day (n=13) or no treatment (controls, n=13) for 4 weeks. Forearm blood ﬂow (FBF) was evaluated by gauge strain plethysmography, and endothelium dependent dilation (EDD) was expressed as the %change of FBF during post-ischemic hyperemia. Levels of ADMA, interleukin-6 (IL- 6), tumor necrosis factor alpha (TNF-�) and soluble vascular cells adhesion molecule (sVCAM-1) were determined with ELISA. Results: Maximum hyperaemic FBF and EDD were increased in ATR (5.8±0.7 and 42.9±4.9 to 6.82±0.8 ml/100ml tissue/min p<0.01 and 58.5±4.8% p<0.05 respectively), but not in vitamin C (7.6±0.8 and 51.3±6.0 to 8.3±0.7 ml/100ml tissue/min and 59.0±7.9% respectively p=NS for all) or control group (6.6±0.5 and 43.9±5.1 to 6.9±0.6 ml/100ml tissue/min and 46.1±6.1% respectively, p=NS for both). ADMA, TNF-�, IL-6, sVCAM-1 and CRP were decreased in ATR (1.21±0.18, 2.51±0.54, 2.27±0.55, 484±31 and 3.84±1.16 to 0.72±0.08µM, 1.62±2.71pg/ ml, 1.36±0.19pg/ml, 363±13ng/ml and 2.34±0.71mg/ml respectively, p<0.05 for all) but not in vitamin C (1.02±0.09, 2.71±0.87, 2.65±0.42, 381±61 and 2.4±0.3 to 0.98±0.07µM, 2.59±0.49pg/ml, 494±32ng/ml and 2.32±0.28mg/ml respectively, p=NS for all) or in controls (0.95±0.07, 1.96±0.22, 2.28±0.59, 450±37 and 2.4±0.7 to 0.93±0.08µM, 2.05±0.19pg/ml, 2.41±0.51pg/ml, 2.21±0.73mg/ml respectively, p=NS). Conclusions: Atorvastatin improves endothelial function, decreases ADMA levels and supresses inﬂammatory process in patients with DM, while vitamin C is ineffective. These ﬁndings suggest that atorvastatin improves endothelial function in diabetic patients, partly by reducing ADMA levels. 1003-190 Lipid Parameters and Risk of Ischemic Stroke in Type 2 Diabetes Mellitus: The Strong Heart Study Jorge R. Kizer, David O. Wiebers, Jack P. Whisnant, James M. Galloway, Thomas K. Welty, Elisa T. Lee, Barbara V. Howard, Richard B. Devereux, Weill Medical College of Cornell University, New York, NY, The Mayo Clinic, Rochester, MN The association between lipids and coronary heart disease is well documented, but that between lipids and ischemic stroke has been inconsistent. Furthermore, the relationships between lipid fractions and ischemic stroke among individuals with diabetes have not been speciﬁcally explored. We investigated these in 1824 American Indians with diabetes and no prevalent cardiovascular disease participating in the population-based Strong Heart Study. Fasting lipids were measured at baseline, and LDL was calculated (Friedenwald). Cox models adjusted for age, sex, BMI, HTN, smoking & alcohol. There were 117 incident ischemic strokes (follow-up 9.2 yrs). A signiﬁcant negative overall association was observed for HDL and a positive one for apoB, while that for LDL was without graded increments across quartiles. The strongest associations occurred for TC/ HDL & LDL/HDL, which were positive but not obviously linear across increasing TC/HDL & LDL/HDL quartiles. Adjustment for diabetes duration and therapy did not meaningfully alter these relations. Our ﬁndings, the ﬁrst in a cohort with diabetes, are consistent with studies in other populations showing lack of a signiﬁcant linear association between TC or LDL and ischemic stroke. HDL showed a signiﬁcant negative overall association, however, and strong, if not eminently linear, positive relationships were present for TC/HDL & LDL/HDL. The latter parameters merit strong consideration in the assessment of ischemic stroke risk in patients with diabetes. Hazard Ratio (95% Conﬁdence Interval) P for Trend Quartile 2 vs 1 Quartile 3 vs 1 Quartile 4 vs 1 Total Cholesterol 0.96(053-1.73) 1.38(0.79-2.39) 1.39(0.80-2.39) 0.122 LDL 1.29(0.69-2.41) 2.08(1.17-3.70) 1.58(0.87-2.88) 0.059 HDL 0.72(0.45-1.17) 0.72(0.43-1.20) 0.50(0.28-0.98) 0.021 Triglycerides 1.52(0.83-2.77) 2.16(1.22-3.79) 1.35(0.75-2.44) 0.247 Apolipoprotein B 0.93(0.51-1.71) 1.17(0.67-2.06) 1.67(0.97-2.85) 0.031 Apolipoprotein AI 0.89(0.53-1.47) 0.79(0.47-1.33) 0.66(0.38-1.14) 0.125 TC/HDL 1.86(0.94-3.67) 2.55(1.34-4.84) 2.58(1.36-4.86) 0.003 LDL/HDL 3.12(1.52-6.40) 3.38(1.66-6.87) 3.19(1.56-6.51) 0.004 ApoB/AI 1.64(0.91-2.97) 1.35(0.74-2.49) 2.02(1.14-3.56) 0.032 POSTER SESSION 1004 Blood Pressure and Ambulatory Blood Pressure Tuesday, March 14, 2006, 8:30 a.m.-Noon Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 1004-191 Job-Strain Induced Workplace Hypertension Is Associated With Obesity and High Normal Blood Pressures at the Physical Checkup Hirokazu Saruhara, Jun-ichi Ishida, Hiroki Ohno, Go Kijima, Yuya Karube, Kazuhiro Takeda, Toru Taniguchi, Iwao Kuwajima, Kazumasa Harada, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan Background: Job strain was shown to be risks for hypertension and for increased LV mass index. Moreover, job strain may be one of the factors associated with masked hypertension, which is characterized with high ambulatory blood pressures and normal blood pressures at the doctor’s ofﬁce. Methods: In order to study the clinical characteristics of the subjects with workplace hypertension and to determine the checkup blood pressures responding to them, 265 public ofﬁcials in the Metropolitan Government Ofﬁce (men, 51%) aged 23-64 years (41.4±10.7 years) were assessed using semi-automated blood pressure monitoring apparatus at the workplace and at the physical checkup. Results: Subjects with workplace hypertension (deﬁned with >140/90mmHg, n=61, 23%) were older (48.5±10 vs. 39.3±10 years old), more in men (68% vs. 46%), with more BMI (23.4±2.7 vs.21.6±3.2kg/m2), higher cholesterol levels (214±33 vs. 194±35mg/ dl), and higher Brinkman’s indices than those without it (n=204). They had higher ACC_2006_8_VascularDisease.indd 350 1/4/06 5:21:24 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 351A Vascular D isease, H ypertension, and P revention blood pressures at the checkup (125±11 vs. 110±11mmHg). The workplace blood pressures were correlated signiﬁcantly with age, BMI, cholesterol levels, family history of hypertension, and the blood pressures at the checkup, which were also signiﬁcant with multiple regression analysis. Moreover, the increases in the blood pressures at the workplace compared to those at the checkup were correlated with age, BMI, family history of hypertension, which were signiﬁcant with multiple regression analysis. Interestingly, hypertension at the checkup deﬁned with >140/90mmHg did not predict work workplace hypertension (sensitivity 10%). However, blood pressures>130/85mmHg at the checkup better predicted the workplace hypertension (sensitivity, 49%; speciﬁcity, 91%; positive predictable value, 63%; negative predictable value, 85%), suggesting that subjects with high normal blood pressures (>130/85mmHg) at the checkup should be carefully followed-up. Conclusions: Workplace hypertension is associated with age, BMI, and family history of hypertension. The subjects with high normal blood pressures at the checkup may need to lose weight, because two-thirds of them have workplace hypertension. 1004-192 Effect of Low-grade Inﬂammation on Arterial Stiffness in Subjects With White Coat Versus Sustained Hypertension A. Zervoudaki, G. Vyssoulis, D. Tousoulis, G. Antonakoudis, C. Vlachopoulos, S. Dimitrakopoulos, Th. Gialernios, C. Stefanadis, Athens University, Hippokration Hospital, Athens, Greece Background: There is now considerable evidence to associate arterial stiffness and inﬂammation with prediction of increased cardiovascular disease. The aim of this study was to investigate and compare possible associations between inﬂammatory markers and indices of arterial stiffness in subjects with white coat (WCH) versus sustained hypertension (SH). Methods: The study involved 163 WCH subjects (mean age 54.3 years, 60 females), 411 SH patients (mean age 54 years, 169 females) and 65 normotensive controls (NC) of similar age (34 females). Aortic stiffness was assessed from the measurement of carotid- femoral pulse-wave velocity (PWV), (Complior SP). High sensitivity C-reactive proteine (hsCRP) and serum amyloid A (SAA) were measured with immunonephelometry. Results: WCH and SH exhibited higher values of hsCRP compared to NC (1.78 ± 1.84 and 1.70 ± 1.82 versus 1.19 ± 1.14, p=0.006 and p=0.004 respectively), but no difference was found between WCH and SH (p=NS). No signiﬁcant difference was found for SAA among and between all groups (p=NS). PWV was higher in WCH and SHP compared to NC (7.38 ± 1.55 and 7.84 ± 1.43 vs 6.81 ± 1.49, p=0.02 and p=0.00001 respectively). Moreover, SHP exhibited signiﬁcant higher values of PWV than WCH (p=0.003). In all groups, PWV was associated positively with SAA (r=0.20 p=0.01, r=0.127 p=0.01, r=0.31 p=0.012 for WCH, SH and NC respectively). hsCRP had a weaker correlation with PWV in SH and in NC (r=0.10 p=0.036, r=0.25 p=0.04 respectively) but no correlation in the WCH group (p=NS). Conclusions: These ﬁndings indicate that WCH and SH subjects have stiffer arteries compared to controls and that inﬂammatory markers might be important determinants of arterial stiffening in these hypertensive groups. 1004-193 Masked Hypertension Is Associated With Impaired Glucose Tolerance and Larger Left Atrium in the Elderly Yuya Karube, Jun-ichi Ishida, Hirokazu Ohno, Hirokazu Saruhara, Go Kijima, Kazuhiro Takeda, Toru Taniguchi, Iwao Kuwajima, Kazumasa Harada, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan Background: Masked hypertension is characterized with greater ambulatory (>135/80 mmHg) than doctor’s ofﬁce blood pressure (BP)(<140/80 mmHg). Recently, SHEAF trial showed increases in the cardiovascular events with masked hypertension. However, prevalence, mechanism, or markers to detect it on the clinical setting remain to be investigated. Methods: To examine the metabolic aspect of masked hypertension, we measured the hemoglobin A1c (HbA1c) levels, performed echocardiography and ambulatory blood pressure measurement (ABPM) in 134 elderly patients aged >60 years (74.9±8.3 years) with treated hypertension. Patients were divided into four groups dependent on the ABPM (135/80 mmHg) and the ofﬁce blood pressures (140/80 mmHg). Results: Uncontrolled hypertension was observed in 29 patients, masked hypertension was in 19 (14%), white-coat hypertension was in 40, and controlled hypertension was in 46. Moreover, among those with normal ofﬁce BP (n=65), 29% patients turned out to have masked hypertension. Patients in the four groups had similar baseline characteristics, but showed signiﬁcant differences in the LV mass index, LA dimension, HbA1c, and ABPM among the groups. The HbA1c level of the masked hypertension group was higher than that of the uncontrolled hypertension group (7.8±1.8% vs. 6.4±1.9%, p=0.003). In order to discriminate the masked hypertension, we compared the masked hypertension with the controlled hypertension. Patients with masked hypertension were characterized with larger ofﬁce pulse pressures (58.0±6.9 vs. 51.5±8.7mmHg, p=0.003), larger LV mass indices (158±58 vs. 129±46g/m2, p=0.055), larger LA dimensions (45±6 vs. 38±4mm, p<0.05), and higher 24-hour ABPM (145±12 vs. 121±10mmHg, p<0.001) than those with controlled hypertension. LV mass was correlated with LA dimension (r=0.49, p<0.001) and the nighttime systolic BP (r=0.29, p<0.001). Conclusions: Masked hypertension may be suspected with higher HbA1c levels, larger ofﬁce pulse pressures, larger LV mass indices, and larger LA dimensions. Thus, association between the HbA1c levels and masked hypertension may implicate an importance of strict BP control in the elderly with impaired glucose tolerance. 1004-194 Non-Dipping Status Is Accompanied by a State of Hypoadiponectinemia, and Arterial Stiffening in Essential Hypertensive Subjects: A Link to Subclinical Atherosclerotic Processes Kyriakos Dimitriadis, Costas Tsiouﬁs, Dimitris Chatzis, Giorgos Chartzoulakis, Carmen Vasiliadou, Dimitris Tousoulis, Pavlos Toutouzas, Christodoulos Stefanadis, Ioannis Kallikazaros, Department of Cardiology, Hippokration Hospital, Athens, Greece Background: The absence of nocturnal blood pressure (BP) fall is related through diverse mechanisms with adverse cardiovascular outcome, while adiponectin is emerging as a marker of atherosclerosis progression. We examined the association between non-dipping status, and plasma concentrations of adiponectin, and arterial stiffness in essential hypertensive subjects. Methods: 148 newly diagnosed untreated non-diabetic patients with stage I to II essential hypertension [98 men, mean age=49 years, ofﬁce BP=150/97 mmHg] underwent 24-h ambulatory BP monitoring, and were classiﬁed as dippers, and non-dippers according to the diurnal variation of >10% between mean daytime, and nighttime systolic, and diastolic BP. Arterial stiffness was evaluated on the basis of carotid to femoral pulse wave velocity (PWV), by means of a computerized method (Complior SP). Moreover, venous blood samples were drawn for estimation of lipid proﬁle, and adiponectin levels. Results: Non-dippers (n=38) compared to dippers (n=110) were older (55±7 vs 49±9 years, p<0.0001), and had higher left ventricular mass index (101±18 vs 119±12 g/m2, p<0.05). In the total population, adiponectin was negatively related to BMI (r=-0.168, p<0.05), 24-h systolic BP (r=-0.194, p<0.05), and PWV (r=-0.280, p<0.001), while it was positively associated with systolic BP fall (r=0.520, p<0.001). Additionally, PWV was related to 24-h systolic BP (r=0.327, p<0.0001), and negatively to systolic BP fall (r=- 0.17, p<0.05). Non-dippers compared to dippers exhibited attenuated adiponectin levels (7.9±3.6 vs 9.7±4.4 µg/ml, p<0.05), and higher PWV values (8.6±1.2 vs 7.7±4.2 m/sec, p<0.05), while did not differ regarding metabolic proﬁle (p=NS). Analysis of covariance revealed that adiponectin, and PWV values remained statistically different between groups after adjustment for confounding factors (p<0.05). Conclusions: Non-dippers hypertensives are characterized by more pronounced activation of pro-atherogenic mechanisms, as reﬂected by low levels of adiponectin, and arterial stiffening. These ﬁndings may partially explain the increased cardiovascular risk associated with non-dipping status, in this setting. 1004-195 Arterial Stiffness in Subjects With White Coat Versus Sustained Hypertension A. Zervoudaki, G. Vyssoulis, P. Pietri, C. Vlachopoulos, A. Deligeorgis, N. Vasilakos, C. Stefanadis, Athens University, Hippokration Hospital, Athens, Greece Background: In the past few years there has been much debate whether white coat hypertension (WCH) is a benign condition or it is associated with increased risk of target- organ damage. The aim of this study was to evaluate indices of arterial stiffness in white- coat hypertensive subjects compared to sustained hypertensive patients (SHP) and to normotensive controls (NC). Methods: The study comprised of 661 non-diabetic subjects. WCH, deﬁned as ofﬁce blood pressure (BP) values higher than normal but within the normal range in ambulatory BP measurements (<135/85 mmHg mean daytime BP recordings) was present in 165 (mean age 54.4 years, 61males) individuals. Sustained mild hypertension was present in 431 patients (mean age 54.2 years, 252 men). The 65 (31 males) NC had similar age. Aortic stiffness was assessed from the measurement of carotid-femoral pulse-wave velocity (PWV), (Complior SP) and determination of arterial wave reﬂection by applanation tonometry on the radial artery that was expressed as augmentation index (AIx), (SphygmoCor 2000). Results: PWV was higher in WCH and SHP compared to NC (7.38 ± 1.55 and 7.84 ± 1.43 vs 6.81 ± 1.49, p=0.02 and p=0.00001 respectively). Moreover, SHP exhibited signiﬁcantly higher values of PWV than WCH (p=0.003). AIx (corrected for heart rate at 75 bpm) was also higher in WCH and in SH subjects compared to controls (27.74 ± 10.77 and 26.39 ± 10.58 vs to 22.18 ±13.21, p=0.005 and p=0.02 respectively). No signiﬁcant difference of AIx was found between WCH subjects and SH patients (p=NS). Conclusions: These results show that WCH population has increased aortic stiffness compared with the NC. It seems that subjects with WCH are at a greater risk of arterial damage than the normotensive population and maybe are in an intermediate risk stage, between normotensive and sustained hypertensive subjects. 1004-196 Hypertensive Response to Exercise Is Related to Insulin Resistance in Non-diabetic Patients With Well Controlled Hypertension Jaemin Shim, Sungha Park, Jin-Bae Kim, Jae Hee Kim, Chanmi Park, Young-Guk Ko, Donghoon Choi, Jong-Won Ha, Se-Joong Rim, Yangsoo Jang, Namsik Chung, Severance Cardiovascular Center, Yonsei University College of Medicine, Seoul, South Korea Background: Hypertensive response to exercise (HRE, deﬁned as systolic BP > 210mmHg in men and systolic BP > 190mmHg in women) may be related to excess stimulation of the sympathetic nervous system and the renin-angiotensin-aldosterone system during exercise and has been reported to be associated with adverse cardiovascular prognosis. Insulin resistance is associated with increased sympathetic activity and elevated angiotensin II which may contribute to the excessive increase in arterial blood pressure during exercise. In this study, we hypothesized that increased insulin resistance will be signiﬁcantly associated with hypertensive response to exercise in non-diabetic, well controlled hypertensive patients. Methods: Two hundred seventy ﬁve hypertensive patients were included in this study and standard Bruce protocols were used for symptom-limited treadmill test. HOMA IR index using serum fasting glucose and insulin was calculated for insulin resistance. Results: There were 79 patients with hypertensive response (age 56.1±9.4 years, N=79) and 196 patients without hypertensive response (age 53.9±8.9 years, N=196). Baseline characteristics were similar in both groups. Insulin resistance, assessed by HOMA index, was signiﬁcantly higher in hypertensive response group as compared to control ACC_2006_8_VascularDisease.indd 351 1/4/06 5:21:24 PM 352A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n (HOMA=2.63 ± 1.57 vs 1.77 ± 0.88, P-value < 0.001). HOMA was an independent predictor of HRE when controlled for age, sex, BMI and baseline SBP [OR=1.96(1.45-2.66), P-value < 0.001]. Also, HOMA was signiﬁcantly correlated with the degree of peak SBP elevation controlled for age, sex, BMI and baseline SBP as well (β=0.302, P-value < 0.001). Conclusions: Insulin resistance is a signiﬁcant determinant of hypertensive response to exercise. Further studies to determine the prognostic signiﬁcance of this ﬁnding is warranted. 1004-197 Contribution of Obesity to Elevated Blood Pressure in Uncomplicated Diabetics: 26-Year of Follow-Up Study Shinji Seto, Katsusuke Yano, Masazumi Akahoshi, Nagasaki University, Nagasaki, Japan, Radiation Effects Research Foundation, Nagasaki, Japan Background: Hypertension and diabetes share a strong relationship to obesity. However, impact of obesity on blood pressure (BP) in diabetics is not fully evaluated. By longitudinal population study, we examined two hypotheses: (1) the rise in BP precedes the clinical appearance of diabetes and (2) obesity accounts for the trend of elevated BP in newly diagnosed, uncomplicated diabetics. Methods: A total of 7,564 subjects have received biennial examinations since 1958 were enrolled. Among them, 170 subjects (92 males, 76 females) were newly diagnosed as diabetes without triopathy during the 26 years of follow-up period (from 1958 to 1984) at the mean age of 51.1±11.6. Longitudinal trends of BP and body mass index (BMI) in these 170 diabetics were compared to those trends in 170 age- and sex-matched non-diabetic controls. Results: Diabetics showed a higher BP than age- and sex-matched non-diabetic controls from 6 years before (128.8±20.6/81.2±12.2 vs. 122.9±20.5/77.3±14.1 mmHg, p<0.05) through 8 years after the diagnosis of diabetes (142.4±20.9/85.2±10.7 vs. 133.0±24.1/81.1±13.3 mmHg, p<0.05). However, diabetics had higher BMI than these non-diabetics for the entire follow-up period (23.4±4.1 vs. 21.7±3.0, p<0.001 at the time of diagnosis). To elucidate the inﬂuence of obesity, we selected another group of 170 non- diabetic controls who matched diabetics for BMI as well as for age and sex. After matching BMI, BP in age- and sex-matched non-diabetics did not differ from the BP in diabetics throughout the follow-up period (at 6 years before the diagnosis: 127.7±23.6/79.5±3.4, at 8 years after the diagnosis: 138.6±24.1/83.0±13.4 mmHg). Conclusions: These results suggested that the rise in BP preceded the clinical appearance of diabetes and, moreover, obesity appears to account for the elevation of BP in uncomplicated diabetes. POSTER SESSION 1005 BNP, CRP and Depression as Risk Predictors Tuesday, March 14, 2006, 8:30 a.m.-Noon Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 1005-198 The Impact of Tumor Necrosis Factor-alpha and 180-Day Mortality in Patients With Acute Decompensation of Severe Low-Output Chronic Heart Failure. Results From the Calcium Sensitizer or Other Inotrope or None in Acutely Decompensated CHF (CASINO) Study Stefanos G. Foussas, Michael N. Zairis, Maria Prodromiti, Evdokia Adamopoulou, Christopher Olympios, Tania Mousouli, Vasilios Tsirimpis, Anastassios Theodosis- Georgilas, John Hatzisavvas, Spyros Argyrakis, Philippos Anastassiadis, Denis V. Cokkinos, Tzanio Hospital, Piraeus, Greece Background-Several studies have shown the independent prognostic value of elevated serum levels of tumor necrosis factor alpha (TNFα) on mortality in patients with chronic heart failure (CHF). However, the possible association of serum TNFα levels with mortality in the setting of acute decompensation of CHF has not thoroughly evaluated. We took the advantage to investigate this possible associations in pts enrolled in the CASINO study. Methods-The CASINO was a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study which investigated the hypothesis that a 24-hr treatment with levosimendan would result in better survival than treatment with either placebo or dobutamine, in 299 patients who were hospitalized for acutely decompensated severe (NYHA class IV) low-output CHF. Venous blood samples for TNFα levels measurements were obtained before pts randomization in all patients. Results-The incidence of 180-day all-cause mortality was 30.1%. Kaplan Maier analysis had shown that there was an increased risk of 180-day death with increasing of the tertiles of serum TNFα levels (15.2%, 31.4%, and 43.9% for First, Second and Third tertile respectively; p<0.001) (Figure 1). Conclusions-The present results suggest that in patients with acutely decompensated severe low-output chronic heart failure serum elevated TNFα levels portend a signiﬁcantly increased risk of 180-day death. 1005-199 Use of N-Terminal-pro-Brain Natriuretic Peptide as a Diagnostic and Prognostic Marker for Ischemic Heart Disease in Patients Presenting to a Rapid Access Chest Pain Clinic Alison R. Muir, Johanne Neill, Karen Darragh, John Dougan, Christopher Patterson, Jennifer A. Adgey, Royal Victoria Hospital, Belfast, United Kingdom, Queen’s University, Belfast, United Kingdom Background: N-terminal-pro-BNP (NT-pro-BNP) is a marker for recurrent ischemic events and mortality in ischemic heart disease (IHD). Its role in diagnosing IHD and predicting outcome in patients with chest pain suggestive of IHD is not established. Methods: NT-pro-BNP was measured in patients presenting to a rapid access chest pain clinic (RACPC) and compared as a diagnostic and prognostic marker to standard methods including exercise stress testing (EST). Results: From November 2004 to January 2005, 447 consecutive patients were enrolled. 73 patients (16.3%) had a positive diagnosis of IHD at myocardial perfusion imaging or cardiac catheterisation. NT-pro-BNP was signiﬁcantly higher among those diagnosed with IHD versus non-IHD (139ng/L [interquartile range 69 to 311] vs 45ng/L [interquartile range 24 to 82] p<0.0001). Patients in the highest NT-pro-BNP quartile were more likely to have IHD (p<0.0001). Following logistic regression analysis, NT-pro-BNP in the highest quartile was a signiﬁcant predictor of IHD, independent of risk factors, renal function, troponin I and EST (hazard ratio for the fourth quartile compared to the ﬁrst 6.6 [95% conﬁdence interval, 1.2 to 36.4]; p=0.019). Patients were followed up for a mean of 9.6 ±0.9 months. Fifty-one (11.4%) reached a composite endpoint of death, myocardial infarction (MI) or revascularization. NT-pro-BNP was signiﬁcantly higher in those who met the endpoint vs those who did not (166ng/L [interquartile range 63 to 314] vs 49ng/L [interquartile range 25 to 91] p<0.0001). In a multivariate Cox regression model, NT-pro-BNP added prognostic information beyond that of the patient’s sex, age, risk factors, electrocardiogram and biochemistry (hazard ratio for the composite endpoint for the fourth quartile compared to the ﬁrst 20.3 [95% conﬁdence interval, 2.6 to 159]; p=0.002). However when EST was included in the regression model, no quartile was a signiﬁcant predictor of outcome (p=0.224). Conclusions: In the setting of an RACPC, NT-pro-BNP quartile is a signiﬁcant independent predictor of IHD. It is associated with the composite endpoint of death, MI and revascularization, but does not provide better prognostic information than an EST. 1005-200 NT-proBNP Predicts Perioperative Cardiac Events in Patients Undergoing Noncardiac Surgery Dae Kyoung Cho, Jeong Hoon Yang, Soo Jin Cho, Jin-Oh Choi, Hak Jin Kim, Seong- Hoon Lim, Sung-Uk Kwon, Joong-Il Park, Jin-Ho Choi, Sang-Chol Lee, Eun-Seok Jeon, Duk-Kyung Kim, Sang Hoon Lee, Kyung Pyo Hong, Jeong Euy Park, Samsung Medical Center, Seoul, South Korea Background: Perioperative cardiac complication is a major cause of morbidity after noncardiac surgery. We hypothesized that NT-proBNP has an additional value in predicting perioperative cardiac complications. Methods: A cohort of 451 patients referred for cardiac consultation before elective noncardiac surgery was enrolled prospectively. The level of NT-proBNP was measured within 2 weeks before surgery. Perioperative cardiac event (POCE) was deﬁned as acute myocardial infarction, congestive heart failure or primary cardiac death within 5 days after surgery. Results: POCEs occurred in 40 (8.9%) of the 451 patients. In multivariate analysis, three independent predictors of POCEs were identiﬁed: preoperative high NT-proBNP (≥ 200 pg/ml), vascular surgery, and ischemic heart disease. Single measurement of preoperative NT-proBNP ≥ 200 pg/ml demonstrated high sensitivity (87.0%) and speciﬁcity (71.5%) for predicting POCE. Next, we compared the performance of predicting POCEs by comparing the area under receiver operating characteristic (ROC) curves. The area under ROC curve was 0.719 for the Revised Cardiac Risk Index. When a high preoperative NT-proBNP (≥ 200 pg/ml) was combined with the Revised Cardiac Risk Index, the prediction power has signiﬁcantly strengthened (area under ROC curve; 0.806 versus 0.719, p = 0.0003, table). ACC_2006_8_VascularDisease.indd 352 1/4/06 5:21:25 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 353A Vascular D isease, H ypertension, and P revention Comparing the areas under ROC curves for prediciting POCE using the technique of Hanley and McNeil Area under curve Standard error 95% CI p lower Upper Revised Cardiac Risk Index 0.719 0.049 0.623 0.815 0.0003 Combined with NT-proBNP 0.806 0.036 0.736 0.876 Conclusions: A high preoperative NT-proBNP (≥ 200 pg/ml) is a novel predictor of POCE and may have an additional role in preoperative cardiac risk index development. 1005-201 Fish Intake Is Associated With Decreased Levels of Inﬂammatory Markers Among People With Metabolic Syndrome: The ATTICA Study Christina A. Chrysohoou, Demosthenes B. Panagiotakos, Christos Pitsavos, Christodoulos I. Stefanadis, University of Athens, Athens, Greece, Harokopio University, Athens, Greece Background: The aim of this work was to investigate the association between ﬁsh consumption and levels of various inﬂammatory and oxidative stress markers, among adults with metabolic syndrome. Methods: The ATTICA study is a cross-sectional survey that enrolled 1514 men (18-87 years old) and 1528 women (18-89 years old) from Attica region, Greece. In this work we focused our interest into those who fulﬁlled the NCEP ATP III criteria for the metabolic syndrome (i.e. 701 men and women). Fasting blood samples were collected and dietary habits (including ﬁsh consumption) were evaluated using a validated food frequency questionnaire. Results: 91% of the people with the metabolic syndrome reported that they consume ﬁsh at least once a week, while mean ﬁsh consumption was 2.2 ± 1.1 servings per week. An inverse correlation was observed between ﬁsh intake and the levels of serum amyloid A (r = -0.18, p = 0.02) and C-reactive protein (r = -0.21, p = 0.01). Compared to non-ﬁsh consumers those who consumed > 300 gr of ﬁsh per week had on average 20% lower CRP and 15%lower amyloid A levels. Signiﬁcant results were also observed when lower quantities (150 - 300 gr / week) of ﬁsh consumed. All associations remained signiﬁcant after various adjustments were made. Finally, cut-off point analysis showed that omega-3 fatty acid intake of 0.7 gr per day was the optimal level that beneﬁts human health, i.e. maximised the likelihood of having the levels of the inﬂammatory markers in the lowest or middle tertile. Conclusions: Fish consumption was independently associated with lower inﬂammatory markers levels, among people with metabolic syndrome. The strength and consistency of this ﬁnding has implications for public health and should be explored further. 1005-202 Leucocyte Count Is a Marker of Arterial Wave Reﬂections in Apparently Healthy Individuals Charalambos Vlachopoulos, Konstantinos Aznaouridis, Ioanna Dima, Nikolaos Ioakeimidis, Nikolaos Alexopoulos, Eleftherios Tsiamis, Gregory Vyssoulis, Christodoulos Stefanadis, University of Athens Medical School, Hippokration Hospital, Athens, Greece Background: Elevated leucocyte count (LC), an index of chronic low-grade inﬂammation, has been associated with subclinical atherosclerosis and future cardiovascular events in several populations. Wave reﬂections (WR) is a measure of arterial elastic properties and an important predictor of cardiovascular risk. The association of inﬂammatory markers such as LC or high-sensitivity C-reactive protein (hsCRP) with WR has not been fully investigated in healthy adults. Methods: We studied 261 apparently healthy individuals (mean age 41 years, 174 males) without any known cardiovascular risk factor or disease, except for smoking. WR were studied using a validated system (Sphygmocor®) that employs high-ﬁdelity applanation tonometry of the radial artery and pulse wave analysis. Augmentation index (AI) was measured as an estimate of WR. LC and level of hsCRP were measured in venous blood in all participants. Results: AI was signiﬁcantly correlated with both LC (r=0.16) and hsCRP (r=0.15), (P<0.05 for both). In multivariate linear regression models, LC and hsCRP were independently associated with AI (P<0.01 and P<0.05 respectively), after controlling for potential confounding factors such as age, gender, blood pressure, height, total cholesterol and intensity of smoking (pack-years). However, the association of AI with LC was more powerful (standardized regression coefﬁcient b=0.14) compared with hsCRP (b=0.11). LC accounted for almost 2% of the variability of AI values, but hsCRP for less than 1%. Conclusion: Our study indicates that in healthy persons LC, which is a widely available and inexpensive test, is a marker of arterial wave reﬂections at least as important as hsCRP. This ﬁnding underscores the pathophysiological role of white blood cells in the cardiovascular homeostasis and has potential implications for their involvement in atherosclerosis. 1005-203 The Impact of Cardiovascular Risk Factors on Oxidative Stress in Humans Salman Ashfaq, Syed Rafﬁ, Steven D. Rhodes, Dean P. Jones, W. Craig Hopper, Jerome L. Abramson, Viola Vaccarino, William S. Weintraub, David G. Harrison, Arshed A. Quyyumi, University of Kansas-School of Medicine, Wichita, KS, Emory University, Atlanta, GA Background: Inﬂammation is an important contributor to the pathogenesis of atherosclerosis, but the clinical role of oxidative stress to this process remains to be proven. We hypothesized that cardiovascular risk factors increase risk of atherosclerotic disease by enhancing oxidative stress. We therefore measured the relationship between the plasma glutathione redox state, an established marker of oxidative stress, and the Framingham risk score (FRS) in healthy adults. Methods: 111 healthy non-smoking, non-diabetic adults, aged 30-65 years, with no clinical atherosclerosis were enrolled. Oxidative stress was estimated as the redox state of plasma glutathione pool (Eh GSH/GSSG) by measurement using HPLC of reduced (GSH) and oxidized (GSSG) glutathione. Framingham risk score was calculated. Results: There were signiﬁcant and independent correlations between Eh GSH/GSSG and age (r=0.25 p=0.008) and systolic blood pressure (r=0.36 p=0.0001). A family history of premature coronary disease (CAD) was also associated with more oxidized levels of Eh GSH/GSSG (-123±7.1 mV vs. -127±7.1 mV, p=0.04). Eh GSH/GSSG also signiﬁcantly correlated with cardiovascular risk measured by the FRS (r=0.23, p=0.02). FRS remained an independent predictor of Eh GSH/GSSG even after adjusting for hs-CRP and other individual risk factors that are not incorporated in the FRS (beta =0.30, p=0.003). Conclusions: In healthy, non-diabetic patients, the glutathione redox state, an established measure of oxidative stress that reﬂects intra-cellular redox, is independently predicted by age, family history of CAD, blood pressure and the FRS. This marker may provide the link between risk factors that constitute the FRS, and the future risk of cardiovascular disease. 1005-204 Platelet Reactivity in Coronary Artery Disease Patients with Depression: Are All Anti-Depressants Equal? Mohammad Urooj Zafar, Karen Hiensch, Gemma Vilahur, Constantin Novoselsky, Daniel Yadagar, Karina Davidson, Jack Gorman, Valentin Fuster, Juan Badimon, Mount Sinai School of Medicine, New York, NY, Columbia University College of Physicians and Surgeons, New York, NY Background A strong relationship exists between coronary artery disease [CAD] and depression. Depressed CAD patients [pt] have more coronary events presumably due to higher serotonin [5HT] mediated platelet reactivity. Anti-depressive therapy has been shown to help reduce coronary events but the mechanism is unknown. We compared platelet reactivity in depressed vs. non-depressed CAD pt and assessed the effect of 4 commonly used antidepressants on platelets. Methods Depressed (13) and non-depressed (15) pt with stable CAD matched for age and sex were enrolled. Blood from each pt was mixed in vitro with saline (control), nefazodone, duloxetine, escitalopram and sertraline. Platelet reactivity was assessed by optical aggregometry in response to ADP (5µM) and 5HT (10µM). Effect of each drug on platelet aggregation was compared with control. Results Depressed CAD pt had higher platelet reactivity vs non-depressed. Except nefazodone, each drug signiﬁcantly reduced 5HT-mediated platelet aggregation, with sertraline being the most potent. No effect on ADP mediated aggregation was seen. Conclusions Depressed CAD pt have increased platelet reactivity which plays an important role in the higher event rate seen in these pts. Different antidepressants inhibit 5HT-mediated platelet reactivity to varying degrees. This highlights the importance of selecting the proper antidepressant in CAD pt, due to the dual effect of improving depressive symptomatology and directly inhibiting platelet reactivity. 1005-205 Detecting Depression in Cardiac Patients: Description of an Innovative System and Preliminary Findings Related to Gender and Age Grant R. Grissom, Richard E. Shaw, Carolyn Gray, Eric Bernier, Sherill Lord, Mark Wexman, Tina Harralson, Veronica Covalesky, Colin Movsowitz, Robert Phillips, Barrie Huberman, Sutter Paciﬁc Heart Centers, San Francisco, Polaris Health Directions, Inc., Fairless Hills, PA Background: Depression is an important, prevalent, and independent risk factor for patients suffering from cardiovascular disease (CVD). In the majority of cases, depression is undetected and/or untreated. When it is discovered, depression has a substantial negative impact on morbidity, mortality and costs in patients with CVD. While the effects of depression are signiﬁcant, demographic characteristics of the patient are important in understanding variations in its impact on health. In patients hospitalized after MI, the hospital mortality rate for women was substantially higher compared to men. The purpose of this study is to describe an innovative system to screen for depression in CVD patients and to present some of the preliminary ﬁndings related to gender and age. Methods: The computerized assessment system is being developed and tested as part ACC_2006_8_VascularDisease.indd 353 1/4/06 5:21:25 PM 354A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n of an NIH grant and consists of a validated questionnaire implemented through control software on a computer. Items are automatically scored and a comprehensive report generated that is immediately available for the patient visit. Six hundred and forty patients (384 men and 256 women) with a diagnosed cardiac disorder who were receiving treatment at one of four cardiac treatment centers were included in the analyses. Results: Nearly twice as many females (F) than males (M) reported having been treated for depression (36.7% vs 19.3%; p<.001). Depression severity (DS score) was inversely related to age among both F (r=-.220; p<.001) and M (r=-.171; p<.001). Mean DS scores for F were signiﬁcantly more severe than for M (t=-4.45; p<.001); mean scores for F were higher than for M in every age group (under 46, 46-55, 56-65, 66-75, over 75). The group that reported the most severe symptoms was women under 46 years of age. Conclusions: There are substantial gender differences among patients relating to depression. In every age group, female patients report more severe depression than male patients, with the most severe symptoms reported by women under the age of 45. Screening for depression using an automated detection system is supported, and should be particularly encouraged for younger female patients, in whom depression may be related to higher mortality rates. 1005-206 Persistence of Depression at Four Months After Myocardial Infarction Is Not Associated With Increased Long-Term Mortality Kapil Parakh, Brett D. Thombs, James A. Fauerbach, David E. Bush, Roy C. Ziegelstein, Johns Hopkins University School of Medicine, Bayview Medical Center, Baltimore, MD, Johns Hopkins University School of Psychiatry, Bayview Medical Center, Baltimore, MD Background: Depression is common after myocardial infarction (MI) and depression at the time of MI has been associated with increased mortality. Despite this, screening for depression has not become widespread in MI care, perhaps because depression may be considered an expected reaction to an MI, one that is likely to be transient and resolve on its own. We examined the resolution and persistence of depression in MI patients and its association with long-term mortality. Methods: Depression was assessed during the initial hospitalization and four months later (in survivors) using the Beck Depression Inventory (BDI) in patients admitted with acute MI from July 1995 to December 1996. A cardiologist blind to the psychosocial status of the subjects evaluated clinical variables. All-cause mortality was assessed in July 2005 using the Social Security Death Index and hospital databases. Results: Of 284 patients enrolled in the study, 202 patients had both baseline and 4- month BDI scores available. Of these 202 patients, 35 (17.3%) had a BDI score > 10 during the initial MI hospitalization, a cutoff score indicating symptoms of at least mild- to-moderate depression and previously shown to predict short-term post-MI mortality. Resolution of depression was observed in 19 of these 35 (54.3%) whose BDI was < 10 when re-assessed at 4 months; this was generally spontaneous resolution since almost no patient was treated for depression in this time period. Although a BDI > 10 during the initial hospitalization was associated with 4-month mortality in this cohort, persistence, resolution, or development of depression at four months was not associated with mortality at 1, 5 or 8 years in Cox proportional hazards models. Conclusions: Depression (BDI > 10) at the time of MI is associated with short-term mortality, but signiﬁcant spontaneous resolution is observed, with > 50% resolution by 4 months. The persistence of depression is not associated with increased long-term mortality independent of other risk factors, perhaps because depression has already had its impact on mortality in the ﬁrst few months after MI and those at greatest risk as a result of mood disturbance may no longer be available for re-assessment after 4 months. 1005-207 Improvement in Exercise Capacity After Inspiratory Muscle Training Is Associated With Reduced Dyspnea and Enhanced Limb Blood Flow in Chronic Heart Failure Ioannis Laoutaris, Athanasios Dritsas, Margaret D. Brown, Athanassios Manginas, Manolis Kallistratos, Peter A. Alivizatos, Dennis V. Cokkinos, Onassis Cardiac Surgery Center, Athens, Greece, University of Birmingham, Birmingham, United Kingdom Background: The effects of inspiratory muscle training (IMT) on aerobic capacity and dyspnea, and its relation to pulmonary, autonomic and limb vasodilator capacity in patients with chronic heart failure (CHF) are being currently reconsidered. Methods: Twenty-seven patients with left ventricular ejection fraction 29± 2%, were studied, after randomization to either a training (TG, n=14) or a control group (CG, n=13). TG and CG exercised at 60% and 15% of sustained maximal inspiratory pressure (SPimax), respectively, 3 times weekly for 10 weeks. Patients underwent pulmonary function tests including lung transfer coefﬁcient (lung diffusion capacity/alveolar lung volume), cardiopulmonary exercise testing and 6-minute walk test. Dyspnea was assessed by Borg scale after the walk test. Sympatho-vagal balance was assessed by heart rate variability from 24 hour ECG recording, and forearm blood ﬂow (FBF) using venous occlusion plethysmography. Results: TG increased inspiratory muscle strength (Pimax, 105.4± 5.3 vs. 79.1± 5, cmH2O, p<0.001), SPimax (511± 42 vs. 308± 28, cmH2O/sec/10 3, p<0.001), peak VO2 (19± 1.2 vs. 17.1± 0.7, ml/kg/min, p<0.05) and walking distance (402.5± 12.7 vs. 375.2± 10.7, m, p<0.005). Dyspnea was reduced (8.1± 0.4 vs. 9.4± 0.4, p<0.001) and hyperemic FBF increased (5.8± 0.7 vs. 4.2± 0.6, ml/100ml/min, p<0.05). CG increased only the Pimax but to a lesser extent (90.6± 9.6 vs. 79.1± 7.5, cm H2O, p<0.05). Conclusion: Improvement in exercise capacity with IMT was associated with amelioration of dyspnea and enhanced peripheral vascular responses in CHF. POSTER SESSION 1014 Cardiac Risk and Risk Reduction Tuesday, March 14, 2006, 8:30 a.m.-Noon Georgia World Congress Center, Hall B1 Presentation Hour: 9:00 a.m.-10:00 a.m. 1014-208 Marked Risk Reduction in Coronary Heart Disease, Stroke and Total Mortality in Women ≥60 Years Old With Low-Dose Pravastatin for Primary Prevention in the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study Kyoichi Mizuno, Haruo Nakamura, MEGA Study group, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan, Mitsukoshi Health and Welfare Foundation, Tokyo, Japan Background: We sought to determine the effect of low-dose pravastatin as a primary prevention for coronary heart disease (CHD), stroke, CHD + cerebral infarction (CI), total mortality and safety in post-menopausal women compared to men, by sub-analysis. The results of the primary analysis will be presented at AHA Scientiﬁc Sessions 2005. Methods: MEGA Study is a prospective, randomized, open-labeled blinded-endpoint (PROBE) study. A total of 7,832 men and post-menopausal women aged 40-70 years with hypercholesterolemia (TC 220-270 mg/dL) and no history of atherosclerotic disease were randomized to either diet alone or diet + pravastatin (10-20 mg daily). The average follow-up was 5.3 years. The primary endpoint was the ﬁrst occurrence of CHD. Secondary endpoints were stroke, CHD + CI, and total mortality. We compared the 5,356 postmenopausal women to the 2,476 men for primary and secondary endpoints and safety. Results: Diet + pravastatin resulted in a similar CHD risk reduction in women and men, compared to diet alone (HR 0.71, 95% conﬁdence interval 0.44-1.14 in women; HR 0.63, 95% conﬁdence interval 0.42-0.95 in men). No interaction between the sexes was found (P = 0.71 for interaction). A similar risk reduction was found for CHD + CI (HR 0.77 for women and 0.63 for men; P = 0.46 for interaction) with diet + pravastatin versus diet alone. Further, no interaction was found for stroke or total mortality. Notably, women ≥60 years old in the diet + pravastatin group showed a marked risk reduction compared to the diet alone group in CHD (HR 0.50; P = 0.016), CHD + CI (HR 0.50; P = 0.003), and stroke (HR 0.42; P = 0.012); no difference was found for total mortality (HR 0.68; P = 0.17). No clinically signiﬁcant difference was found between the groups in women for severe adverse events or cancer. Conclusions: In the Japanese women and men in the MEGA study, diet + pravastatin produced a similar risk reduction in CHD (29% and 37%, respectively); CHD + CI (23% and 37%, respectively); stroke (24% and 9%, respectively); and total mortality (35% and 20%, respectively). Of note, however, are the marked risk reductions in CHD (50%), CHD + CI (50%), and stroke (58%) with diet + pravastatin in women ≥60 years old. 1014-209 Very Low-Fat Japanese Diet and Daily Exercise Reduce Plasma Lipid Levels With Small Dose of Statins and is Effective for Regression of Coronary Atherosclerosis Keiichi Nakagawa, Issei Komuro, Chiba University Graduate School of Medicine, Chiba, Japan Background: Lifestyle and lipid drugs separately beneﬁt patients with coronary artery disease (CAD). As the population of CAD is increasing in Japan as their lifestyle is westernized, traditional Japanese diet is considered as ideal for preventing CAD. Thus, we made very low-fat Japanese diet recipe for 10 full days and evaluate the effect for lipid-lowering and for disease progress. Methods: The recipe was used to educate 52 patients (35 males, mean age 61±9 years) with CAD or carotid artery sclerosis by nutritionists and to serve foods for in-hospital patients. Small dose of statins was prescribed and daily exercise was instructed to all the patients. Plasma total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) cholesterol at 1 month after the treatment introduction were compared to those at baseline. Among all, 12 patients who showed myocardial perfusion abnormalities by 13N-ammonia PET were followed-up by repeated PET after 1-year treatment. Results: The diet has a option of 1800 and 1400 kcal of total energy depending on the patient’s ideal body weight and contains approximately 10% fat, 20% protein, and 70% carbohydrates prepared with variety of vegetables, beans, ﬁshes and small amount of meats. No oil was added for preparation and the ratio of polysaturated to saturated fat was 1.0:0.5. Every patient took statins but only 10 patients exercise daily, 12 did 2-3 times a week, and the remaining 30 did not. Plasma TC, LDL-C, HDL-C and TG decreased by 24%, 34%, 6%, and 14%, respectively, in all the patients. Reduction rate of LDL-C in those treated with Simvastatin was 36%, which was 10% greater than that reported in the large scale cohort study in Japan (J-LIT). In those who exercise daily, LDL-C decreased by 43% and HDL-C increased by 1%, which were greater effect than those who exercise less (29% and -1%) or nothing (32% and -10%). Perfusion abnormality by PET was improved in 9, remained unchanged in 2, worsened in 1. Conclusions: Intake of very low-fat Japanese diet may reduce the dose of statins for preventing CAD and daily exercise inhibits the reduction of HDL-C. ACC_2006_8_VascularDisease.indd 354 1/4/06 5:21:26 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 355A Vascular D isease, H ypertension, and P revention 1014-210 Combination Statin and Fibrate Therapy Improves Lipoprotein Subparticle Proﬁles in Diabetic Patients With Mixed Dyslipidemia: The DIACOR Study Heidi Thomas, Jonathan R. Jensen, Jeffrey L. Anderson, Farangis Lavasani, Robert R. Pearson, Benjamin D. Horne, Joseph B. Muhlestein, LDS Hospital, Salt Lake City, UT, University of Utah, Salt Lake City, UT Background: Diabetes (DM) is a strong risk factor for atherosclerosis and is often characterized by dyslipidemia. Statins and ﬁbrates improve lipoprotein metabolism by different but potentially complementary mechanisms. Besides acting on traditional lipids, statins and ﬁbrates may also exert beneﬁcial effects on various pro- and anti-atherogenic lipid subparticles. To assess this possibility, we evaluated combination therapy on lipid subparticles in the DIACOR Study. Methods: Patients (pts) with type II DM and no history of coronary heart disease were evaluated (N=498). Eligible pts underwent a 6-8 week washout period of all lipid lowering medications and were enrolled if they demonstrated mixed dyslipidemia (having 2 out of 3: LDL >100, triglycerides >200, or HDL <40). Pts were randomized to: simvastatin (S) 20 mg, fenoﬁbrate (F) 160 mg, or combined (C) S 20 mg and F 160 mg. Lipid subparticles were assessed 12 weeks post randomization by the Vertical Auto Proﬁle (VAP). Results: A total of 300 pts (age = 61±11 yrs, males = 55%) were randomized. VAP parameters for baseline and 12 weeks are shown in the Table (*p<0.05: baseline vs. 12 week within treatment arm): Baseline 12 Week % Change p-value F S C F S C F S C F v S F v C S v C Lp(a) 5.4 4.7 6.3 5.5 5.4 5.6 +2% +15% -11% 0.8 0.7 0.3 HDL2 6.7 6.9 6.9 7.1 7.1 6.7 +6% +3% -3% 0.9 0.07 0.1 HDL3 32.2 31.7 30.7 34.8 32.7 33.6 +8% +3% +9%* 0.7 0.9 0.5 LDL Pattern B 82.6 86.4 81.1 65.7 58.9 50.6 -20%* -32%* -38%* 0.5 0.1 0.7 IDL 22.7 26.2 24.0 18.6 14.6 15.6 -18%* -44%* -35%* 0.005 0.16 0.4 Dense VLDL 17.2 17.9 19.7 10.4 11.3 9.5 -40%* -37%* -52%* 0.9 0.001 <0.001 Conclusion: In this trial of mixed dyslipidemic diabetic pts, C was more effective in changing a variety of other cardiovascular risk markers and was the only therapy that lowered Lp(a). The potential for positive cardiovascular beneﬁts of combined therapy with both statin and ﬁbrates should be further evaluated in this high risk population. 1014-211 Risk Assessment and Risk Reduction by Perindopril in Patients With Normal Left Ventricular Function or Previous Revascularization in the EUROPA study Willem J. Remme, Jaap W. Deckers, Dick Goedhart, Maarten L. Simoons, Kim M. Fox, Roberto Ferrari, Michel Bertrand, Sticares Cardiovascular Research Institute, Rhoon, The Netherlands Background: In the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA), perindopril 8 mg daily signiﬁcantly reduced cardiovascular (CV) death, non-fatal myocardial infarction (MI) and resuscitated cardiac arrest by 20%,compared to placebo, after a follow-up of 4.2 years in patients (pts) with stable coronary artery disease (CAD). Subsequent risk proﬁling showed a consistent risk reduction among high, intermediate and low risk pts. Whether this pertains in pts with a normal left ventricular (LV) function or previous revascularisation is unknown. Methods: Of the 12218 pts included in EUROPA, 6878 had a quantiﬁed LV ejection fraction (LVEF) ≥ 40% and 6709 a previous revascularization at baseline. A risk score (tertiles) was composed of the following independent risk factors identiﬁed by multivariate analysis: age >65 years, male gender, BMI>30kg/m2, symptomatic CAD, previous stroke or peripheral vascular disease, previous myocardial infarction, diabetes, smoking, high cholesterol, family history of CAD, systolic blood pressure >130 mmHg, creatinine clearance ≤ 80ml/min. Results: In pts with LVEF≥ 40% the rates of CV death and MI were 5.4%, 9.5% and 14.7% in low, intermediate and high risk tertiles of the placebo pts, respectively, and 4.5%, 6.6% and 13.7% in comparable risk tertiles in perindopril pts, resulting in 17%, 30% and 6% risk reductions by perindopril in low , intermediate and high risk pts, respectively (interaction p-value 0.375). In revascularized pts, CV death and MI occurred in 4.2%, 7.1% and 12.9% in the low, intermediate and high risk placebo tertiles, respectively, and in 4.0%, 5.3% and 10.8% of comparable perindopril tertiles, resulting in a 5%, 26% and 16% risk reduction in favour of perindopril in the low, intermediate and high risk groups, respectively ( interaction p-value 0.739). Conclusions: Treatment beneﬁt with perindopril is consistent among low, intermediate and high risk pts with normal LV function or previous revascularization without heterogeneity of treatment effect. 1014-212 Clinical Signiﬁcance of Large and Small Low-Density Lipoprotein-Cholesterol Concentrations in Patients With Various Types of Coronary Heart Diseases Shinji Koba, Fumiyoshi Tsunoda, Tsutomu Hirano, Yasuki Ito, Yuuya Yokota, Yoshihisa Ban, Takatoshi Sato, Makoto Shoji, Hiroshi Suzuki, Takashi Katagiri, Showa University School of Medicine, Tokyo, Japan, Denka Seiken Co. Ltd, Tokyo, Japan Background: Predominance of small dense low-density lipoprotein (SD-LDL) is a powerful risk factor for coronary heart disease (CHD). However, it remains unclear how closely large LDL-cholesterol (L-LDL-C) and SD-LDL-C concentrations are associated with various types of CHD. Methods: We measured the LDL size by gradient gel electrophoresis and quantiﬁed SD-LDL-C concentrations by a newly developed rapid assay using heparin-magnesium precipitation in 225 consecutive CHD patients without any lipid-lowering medication and 142 healthy middle-aged subjects as controls. L-LDL-C was estimated by subtracting the SD-LDL-C concentration from the LDL-C concentration. Results: The LDL size was markedly smaller, SD-LDL-C levels were signiﬁcantly higher, and L-LDL-C levels were somewhat lower in CHD patients than in controls of both sexes, whereas LDL-C levels were comparable between CHD and controls. Both LDL-C and SD- LDL-C levels were signiﬁcantly higher in a subpopulation of 84 patients with acute coronary syndrome (ACS) than in other patients groups, whereas L-LDL-C levels were comparable between ACS and controls. The LDL size and high-density lipoprotein-cholesterol (HDL- C) were not found to vary among the patients. Not L-LDL-C but SD-LDL-C increased as the number of diseased vessels or Gensini atherosclerosis score increased. Among the 123 stable CHD patients, the SD-LDL-C was signiﬁcantly higher in the 65 severe cases requiring coronary revascularization than the 58 mild cases (46.2 +/- 2.9 vs 34.1 +/- 2.3 mg/dL, Mean+/-SE), while L-LDL-C was comparable between the two groups (85.9 +/- 3.8 vs 82.7 +/- 3.2 mg/dL). Multiple logistic regression analysis revealed that SD-LDL-C levels were signiﬁcantly associated with the clinically severe cases independently of LDL-C, HDL-C, apolipoprotein B, and HbA1c. Conclusions: Both SD-LDL and elevated SD-LDL-C were potent risk factors for CHD. The SD-LDL mass plays a more important role in the progression of CHD than the LDL size, and the SD-LDL-C concentration serves as a powerful surrogate marker for the prevention of CHD. 1014-213 Hypertension and Hypercholesterolemia: Achievement of Treatment Targets in a Primary Prevention Population Claudia Bambs, Mónica Acevedo, Lorena Orellana, Verónica Kramer, Gastón Chamorro, José Antonio Rodriguez, José Miguel Castellón, Ramón Corbalán, Catholic University School of Medicine, Santiago, Chile Background: Despite of the evidence that treatment of hypertension (HTN) and hypercholesterolemia (HCHOL) decreases coronary heart disease (CHD) morbi-mortality, a signiﬁcant number of patients remain suboptimally treated.Objectives: To determine the percentage of subjects that achieve treatment goals for HTN (JNC VII) and HCHOL (ATP III) in an urban population. Methods: Prospective study in 1576 subjects without atherosclerotic disease (64% male, aged 52±12 yo). Participants had an interview about CHD risk factors and current pharmacological therapy. We measured systolic (SBP) and diastolic (DBP) blood pressure in 2 days, a fasting lipid proﬁle and glycemia. Treatment targets used were: SBP <130 mmHg, DBP <85 mmHg, Total cholesterol <200mg/dl, and LDL < 130 mg/dl for subjects with ≥ 2 CHD risk factors and < 160 mg/dl for those with < 2 CHD risk factors. Results: Nineteen percent of subjects were at low risk and 81% at intermediate-high risk according to ATP III-modiﬁed Framingham risk score. HTN was present in 25% and HCHOL in 53%. The table shows percentage of treated subjects and rate of target achievement: Hypertension High Total Cholesterol Levels High LDL cholesterol levels Treated Subjects (%) 344 (87%) 285 (34%) 285 (34%) Target Achievement (%) 130 (38%) 134 (47%) 178 (62%) Conclusions: In this intermediate-high risk population there is a good percentage of treated HTN, however, achievement of targets still remains low. By contrast, treatment of HCHOL remains very low, but the achievement of goals is better compared to HTN. Effective educational and therapeutic strategies are needed to enhance the awareness, treatment, and achievement of treatment goals. 1014-214 Effect of Post Fat Loading Remnant Like Particles- Cholesterol on Prognosis in Patients With Coronary Artery Disease Tomoya Onodera, Toshiaki Yano, Aritaka Makino, Hirofumi Sugiyama, Moritake Iguchi, Taku Yokoyama, Hayato Otani, Akira Shimane, Koichiro Murata, Akinori Takizawa, Shizuoka City Shizuoka Hospital, Shizuoka, Japan Background: Remnant like particles-cholesterol (RLPC) has been related to atherosclerosis. Postprandial hyperlipidemia has also been proposed to be atherogenic. We evaluated the contribution of RLPC before and after fat loading to the prognosis of coronary artery disease (CAD). Methods: From July 1996 to July 1997, RLPC levels at fasting and 4 hours after fat loading (oral 40g fat/m2 body surface area) were measured in 269 patients with CAD on the day before coronary angiography. The patients had >50% coronary stenosis on coronary angiography, and141 of them had previous myocardial infarction. Number of vessels diseased (VD), glycosylated hemoglobin, fasting blood glucose, insulin, high density lipoprotein-cholesterol (HDL-C), total cholesterol, triglyceride, lipoprotein(a) were also evaluated. The patients were followed for 7±2years. Cardiac death or revascularization for a new ischemia during follow up was evaluated as cardiac event. Results: Cardiac death was observed in 14 patients (5%) and revascularization was observed in 86 patients (32%) during the follow up period. Patients with cardiac death or revascularization had higher post fat loading RLPC (8.2±5.0 vs 6.6±4.0 mg/dl, P<0.02), lower HDL-C (40±10 vs 44±12 mg/dl, p<0.02), and higher VD (1.9±0.8 vs 1.5±0.9, p<0.01) than patients without cardiac events. Fasting RLPC was not different between patients with cardiac events and those without (4.4±2.6 vs 4.0±2.2 mg/dl, P:NS). No other variables showed signiﬁcant differences between the groups. In Cox hazard model, only higher post fat loading RLPC (p<0.05) and higher VD (p<0.01) were signiﬁcantly associated with cardiac events. Conclusions: RLPC after fat loading was associated with further cardiac events in patients with CAD. Therapeutic intervention aiming at lowering postprandial RLPC may be warranted. ACC_2006_8_VascularDisease.indd 355 1/4/06 5:21:26 PM 356A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n ORAL CONTRIBUTIONS 841 Clinical Aspects of Endothelial Function Tuesday, March 14, 2006, 9:00 a.m.-10:30 a.m. Georgia World Congress Center, Room B314 9:00 a.m. 841-3 Selective Cyclooxygenase-2 Inhibition by Celecoxib Abrogates the Acute Smoking-Induced Vascular Dysfunction Charalambos Vlachopoulos, Athanassios Bratsas, Konstantinos Aznaouridis, Nikolaos Ioakeimidis, Panagiotis Xaplanteris, Nikolaos Alexopoulos, Christodoulos Stefanadis, University of Athens Medical School, Athens, Greece Background: The cardiovascular toxicity that is associated with cyclooxygenase-2 (COX- 2) inhibitors is perhaps not a class effect, but may be rather limited to certain drugs in the class. Endothelial function and aortic stiffness are predictors of cardiovascular risk. The effect of celecoxib, a selective COX-2 inhibitor on acute smoking-induced vascular impairment is unknown. Methods: We studied the effect of 200 mg of celecoxib in 12 healthy smokers (mean age 29.5 years) according to a randomized, double-blind, crossover fashion. Endothelial function and aortic stiffness were evaluated with ﬂow-mediated dilatation (FMD) of the brachial artery and carotid-femoral pulse wave velocity (PWV) respectively. Measurements were done before celecoxib/placebo and immediately after a regular cigarette (tar 14 mg, nicotine 1 mg) that was smoked 3 hours after drug administration. Results: Celecoxib blunted the smoking-induced increase in systolic BP (p<0.05), but not in diastolic BP (p=NS). Celecoxib abrogated the smoking-related decrease in FMD (decrease by 2.1 vs 0.6%, p<0.05, left ﬁgure). Moreover, the increase in PWV after smoking was signiﬁcantly lower with celecoxib (increase by 0.69 vs 0.29 m/sec, p<0.05, right ﬁgure). Conclusion. Selective COX-2 inhibition by celecoxib abolishes the endothelial dysfunction and aortic stiffening that is induced acutely by smoking. This ﬁnding provides further insights into the cardiovascular proﬁle of this drug. 9:15 a.m. 841-4 5-Methyl-Tetrahydrofolic Acid Rapidly Improves Endothelial Function and Superoxide Production in Human Atherosclerosis: Effects on Tetrahydrobiopterin- Dependent eNOS Coupling Charalambos A. Antoniades, Cheerag Shirodaria, Paul Leeson, Justin Lee, Nicolas Warrick, Joseph De Bono, David Taggart, Chandi Ratnatunga, Ravi Pillai, Keith M. Channon, University of Oxford, Oxford, United Kingdom Background: Uncoupled endothelial nitric oxide synthase (eNOS) appears to be a source of superoxide radicals (SOO) in human atherosclerosis. We hypothesized that 5-methyl- tetrahydrofolic acid (5MTHF), the active metabolite of folic acid, may improve eNOS coupling by preventing the intracellular oxidation of eNOS cofactor tetrahydrobiopterin (BH4), decreasing in this way SOO production in human vessels. Methods: Fifty-two patients undergoing CABG were randomized to receive intravenous bolus 5MTHF (0.13 mg/Kg BW) or placebo preoperatively, 45 minutes before graft harvesting. Vascular superoxide production was determined in paired samples of human saphenous veins (HSV) and internal mammary arteries (IMA) using 5µM lucigenin chemiluminescence, in the presence or absence of NOS inhibitor LNAME. Vasomotor responses to acetylcholine (Ach) and nitroprusside (SNP), and vascular biopterin levels were also determined Results: 5MTHF improved vasomotor response to Ach (Fig a) and decreased SOO- production in both HSV and IMA (1.0±0.15 and 0.97±0.15 RLU/Sec/mg in 5MTHF vs 2.27±0.37 and 5.01±0.62 RLU/Sec/mg in placebo, p<0.01 for both). LNAME reduced SOO signal in both HSV and IMA in placebo group, an effect reversed by 5MTHF (Fig b). 5MTHF increased total biopterins (tBIO), BH4 and the tBio/BH4 ratio (Fig c). Conclusions: 5MTHF rapidly increases nitric oxide bioavailability, improves eNOS ‘coupling’ and decreases superoxide production in human vessels by preventing intracellular BH4 oxidation in vivo. 9:30 a.m. 841-5 Mortality, Cause of Death, and Coronary Endothelial Function During Long-Term Follow-Up Among Hypertensive African and Caucasian Americans Jan L. Houghton, Mikhail T. Torosoff, Albany Medical College, Albany, NY Background: Previous studies demonstrated worse cardiovascular (CV) prognosis among Caucasians with abnormal coronary endothelial function (CEF). There is no comparable published data in African Americans (AA). Methods: We initiated a prospective study over 12 years ago to examine the inﬂuence of race, hypertension (HTN), and left ventricular hypertrophy (LVH) on CEF. CEF testing was performed during coronary angiography using endothelium-dependent and -independent agents, acetylcholine and adenosine. The cohort of 334 patients is in long-term follow-up. Using medical records, public resources, the Social Security Death Index, the National Death Index, and death certiﬁcates, we analyzed interim mortality in the group. Results: Of 334 subjects (125 AA) with a mean follow-up of 10±2.5 y, the vital status of 308 (92%) is known. Of 26 unknowns, 15 are AA. Assuming all of the unknowns are still alive (since none was detected by national and state databases), 87.6% Caucasians vs 79.2% AA (p=0.06) are projected to remain alive. Assuming similar proportionality of vital status within known and unknown groups, 87.1% Caucasians vs 76.8% AA are alive (p=0.022). Of the dead, 65% Caucasians vs 89% AA had LVH by 2D echo (p=0.098). Among AA, 14 of 26 deaths (53.8%) were of CV etiology, 2 from cancer (7.7%), 2 from other organ system failure (7.7%), 3 from accidental causes (11.5%), and 5 undetermined (19.3%). Among Caucasians, 7 of 26 deaths (26.9%) were of CV etiology, 3 from renal failure (11.5%), 7 from cancer (26.9%), 8 from other organ system failure (30.8%), and 1 undetermined (3.9%). Among the deceased, age and mean follow-up time were similar (62.2±2 y in AA vs 66.2±2 and 6.2±0.5 y vs 6.8±0.8). Coronary ﬂow reserve was similar (2.5±0.2 vs2.6±0.2). However, CEF responses were depressed in AA (85±22% increase in coronary blood ﬂow after acetylcholine vs 117±17%, p= 0.28). Conclusions: Worse CEF, increased prevalence of LVH, poorer overall prognosis, and markedly increased CV cause of death were found among AA in the hypertensive cohort. Disease states found to be linked with premature mortality in ethnic groups should be targeted for early screening and treatment. 9:45 a.m. 841-6 PPAR-γ Agonist Improves Endothelial Function in Patients With Metabolic Syndrome: Pivotal Role of NOx and Inﬂammation Sung-Ji Park, Dong-Ju Choi, Choong-Hwan Kwak, Jin-Yong Hwang, Gyeongsang National University College of Medicine, Jinju, South Korea, Seoul National University College of Medicine, Bundang, South Korea Background: Nitric oxide (NO), which is a potent vasodilator substance and is thought to have antiatherosclerotic properties. On the other hand, NO activity reduces in metabolic syndrome and metabolic syndrome is associated with induction of a proinﬂammatory and oxidative stress, and endothelial dysfunction. Endothelial dysfunction is an important early sign of atherosclerosis in metabolic syndrome. The aim of this study was to investigate the effect of pioglitazone on endothelial function in terms of plasma NOx, circulating inﬂammatory markers and autonomic nervous system. Methods: We randomized 40 subjects with the metabolic syndrome assigned to receive 15mg of pioglitazone per day (PIO, n=21) during 3 months or placebo group (PLA, n=19). To estimate the endothelial function, Flow-mediated dilatation (FMD) were measured in brachial artery by using vascular ultrasound. Plasma NOx and inﬂammatory markers, as ESR, hsCRP and interleukin-6 were measured before and at the 12-week follow-up. Plasma NOx was measured by Griess method. Lymphocytes were isolated from patients and real-time RT-PCR and immunoblotting were done to estimate the expression of ßARK1 in the lymphocytes. Results:After 12 weeks of therapy, FMD, reﬂecting the endothelial function and responsiveness to blood ﬂow, improved in PIO (from 6.7±6% to 11.7±5%: P< 0.01), but not in PLA, whereas NMD, reﬂecting the vasodilatation by smooth muscle, was not changed signiﬁcantly in both group. The level of plasma NOx was increased in PIO (from ACC_2006_8_VascularDisease.indd 356 1/4/06 5:21:27 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 357A Vascular D isease, H ypertension, and P revention 67.7±30 nmol/dL to 92.9±41 nmol/dL : P< 0.001), but not in PLA. Plasma levels of hsCRP and IL-6 were dropped signiﬁcantly (from 2.6±2.3 mg/L to 1.2±1.3 mg/L and 1.7±2.1 pg/mL to 0.7±0.5 pg/mL: P<0.05) in PIO, not in PLA. The levels of ßARK1 (PLA from 0.0061±0.0023 ng to 0.0075±0.0031 ng, PIO from 0.0024±0.002 ng to 0.0015±0.001 ng, p=ns) were not different dropped signiﬁcantly. Conclusions: Administration of PPAR-γ agonist in metabolic syndrome patients improves endothelial function enhancing the production of NOx and reducing proinﬂammatory markers but not related to sympathetic regulation. PPAR-γ agonist may be able to modulate the progression of atherosclerosis. 10:00 a.m. 841-7 Increased Dilator Response to Nitrate in Contrast to Decreased Flow Mediated Dilatation in Migraineurs: An Ultrasonographic Evaluation of Brachial Artery Ertan Yetkin, Handan Ozisik, Cemal Ozcan, Yuksel Aksoy, Hasan Turhan, Inonu University Faculty of Medicine, Malatya, Turkey Background: It has been known that in a migraine attack intracranial and extracranial arteries on the headache side dilate and when the migraine attack has subsided, the intracranial arteries show segmental narrowing. We hypothesized that patients with migraine had an underlying systemic vasomotion abnormality and there might be an increased nitrate mediated vasodilatory response in the brachial artery of migraineurs. Accordingly we aimed to measure endothelium dependent and independent functions of brachial artery in migraineurs and healthy subjects. Methods: Twenty four patients who fulﬁlled the diagnostic criteria of migraine were enrolled in the study. Twenty six age and sex matched healthy control subjects comprised the control group. Flow mediated dilatation and nitrate mediated dilatation were measured in all patients and control subjects by means of brachial artery ultrasonography. Results: Flow mediated dilatation of patients with migraine was signiﬁcantly lower than that of control subjects (7.6±3.7% vs 10.4±3.5% respectively p=0.008). However nitrate mediated dilatation in migraineurs was signiﬁcantly higher than that of nonmigraineurs (25% vs 14% respectively p<0.001). Conclusions: We have shown that migraineurs have decreased endothelium dependent function whereas increased nitrate mediated response in their brachial artery. Our results may suggest that the mechanism underlying migraine is a diffuse vascular vasomotion abnormalities and migraine is likely to be a local manifestation of systemic vascular abnormality rather than a primary cerebral phenomenon. 10:15 a.m. 841-8 Endothelial Function Is Increasingly More Impaired in the Leg Compared to the Arm in Groups With Increasing Risk: Assessment Using Magnetic Resonance Imaging Harry A. Silber, Pamela Ouyang, David A. Bluemke, Brad C. Astor, Sandeep N. Gupta, Thomas K. Foo, Joao A.C. Lima, Johns Hopkins University School of Medicine, Baltimore, MD, General Electric Healthcare Technologies, Milwaukee, WI Background: It is unclear why atherosclerosis involves lower extremities more severely than upper extremities. We hypothesized that there are regional differences in endothelial function that could explain regional differences in atherosclerosis development. Methods: Using magnetic resonance imaging, we directly measured shear rate at rest and during reactive hyperemia (endothelial-dependent) in brachial and femoral arteries of 46 subjects - 14 young (21-33 yrs) healthy (YH), 18 older (>50 yrs) healthy (OH), and 14 older type 2 diabetic (OD) subjects. Change in systolic shear rate (ΔSSR) from baseline to peak hyperemia was calculated. Leg endothelial function relative to arm was assessed by ΔSSR-leg/ΔSSR-arm. Results: The groups were similar with regard to resting femoral radius, brachial radius, femoral shear rate, ratio of femoral-to-brachial radius, and ratio of femoral-to-brachial shear rate. Resting brachial shear rate was lower in OH than YH (358±110 vs 441±137 sec-1, p=.04), but there were no differences between groups during hyperemia. During hyperemia, ΔSSR-leg/ΔSSR-arm was lower in OD (.29±.20) than OH (.52±.42, p=.030), and lower in OH than YH (.82±.47, p=.039, Figure). Conclusions: Endothelial vasodilator function is increasingly more impaired in the leg than in the arm with increasing level of cardiovascular risk. Differences in regional endothelial function may underlie differences in atherosclerosis development in different arterial beds. ORAL CONTRIBUTIONS 842 Risk Assessment: Metabolic Syndrome and Diabetes Tuesday, March 14, 2006, 9:00 a.m.-10:30 a.m. Georgia World Congress Center, Room B407 9:00 a.m. 842-3 Risk Factors for Cardiovascular Disease in Patients with Prediabetes Paul Kolm, William S. Weintraub, David Ziemer, Mary Rhee, Jovonne Foster, Jane Caudle, Lawrence S. Phillips, Emory University, Atlanta, GA Background: 41 million Americans have prediabetes, but their risk of associated cardiovascular disease (CVD) is not known. We assessed CVD risk factor proﬁles in adults with impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Methods: 385 community subjects underwent glucose tolerance tests. Risk factors were selected to be multiethnic, and dichotomized at the upper quintile of normal glucose tolerance (NGT) except for waist circumference (dichotomized > 35 females and > 40 males). Logistic regression was used to assess CVD risk factors in prediabetes groups compared to the NGT reference group. Results: The subjects were 67% female, 53% White, 47% Black, and had average age 47 years and BMI 31; 251 were NGT, 26 had IGT alone (2 hr glucose 140-199), 48 had IFG alone (fasting glucose 100-125), 39 had IGT+IFG, and 21 had diabetes (one-third found only by glucose tolerance test). IFG-alone subjects were at increased risk only for ALT, IGT-alone subjects were at increased risk only for waist circumference, but IGT + IFG subjects were at increased risk for waist circumference, systolic pressure, and ALT. Moreover, for IGT + IFG subjects, odds ratios for CVD risk factors were greater than one for all measures (Table 1). Conclusions: Individuals with prediabetes have increased CVD risk. However, IGT with IFG appears to confer increased risk compared to subjects who have only IGT or only IFG. The search for individuals at high risk for CVD should include measurement of both fasting and 2-hour glucose levels. CVD Risk Factor Odds Ratios and 95% Conﬁdence Intervals for IGT-alone, IFG-alone and IGT+IFG Risk Factor IGT-alone IFG-alone IGT+IFG Waist circumference 4.17(1.62-10.73)* 1.69(0.82-3.47) 2.71(1.18-6.24)* sBP(> 130) 1.24(0.47-3.26) 1.67(0.80-3.46) 2.19(1.01-4.76)* ALB-CR(> 12) 2.39(0.98-5.83) 1.07(0.46-2.48) 1.37(0.56-3.30) ALT(> 24) 1.33(0.52-3.43) 5.88(3.01-11.51)* 7.00(3.28-14.93)* CRP(> 4.7) 0.55(0.19-1.60) 1.36(0.61-3.01) 1.19(0.51-2.81) LDL(> 130) 0.99(0.40-2.43) 0.60(0.27-1.29) 1.30(0.60-2.79) * p < 0.05, 95% CI does not include 1 9:15 a.m. 842-4 Cardiovascular Risk Assessment can Be Improved Using Components of the Metabolic Syndrome and Other Risk Markers: The European Concerted Action Project Tora Leong, Anthony P. Fitzgerald, Catherine McGorrian, Ian M. Graham, On behalf of the European COMAC Group, Adelaide & Meath Hospital, Dublin, Ireland, University College Cork, Ireland Background: Cardiovascular risk assessment in healthy subjects is mainly based on conventional risk factors for cardiovascular disease (CVD). The added value of the metabolic syndrome (MS) and other risk markers needs further examination. Methods: We examined data from The European Concerted Action Project: Homocysteinaemia and Vascular Disease, a multicenter case control study. The diagnostic ability of each CVD risk marker was tested step-wise by comparing their areas under the ROC curve. Firstly, the added value of either adding the MS as a categorical variable, or its components as continuous variables, was compared. Secondly, we examined the effect of adding other risk markers. The AHA 2005 deﬁnition of the MS was used with BMI ≥ 30 used as a proxy for increased waist circumference. Results: Of the 1,550 patients, 209 were excluded due to missing data. Table 1 illustrates the added value of each risk marker. Similar results were obtained when the SCORE risk equation was used instead of conventional risk factors. Table 1 Model Area under the ROC curve 95% CI P value (compared with previous model) Conventional risk factors (age, sex, blood pressure, smoking, total & LDL cholesterol) 0.727 0.700, 0.754 - Above + MS (categorical) 0.744 0.718, 0.771 0.004 Conventional risk factors + MS components (HDL, triglycerides, body mass index, glucose) 0.773 0.748, 0.798 <0.0001 Above + Family History 0.776 0.751, 0.801 0.267 Above + White cell count 0.781 0.757, 0.806 0.028 Above + Apolipoprotein B/AI ratio 0.782 0.757, 0.807 0.638 Above + Homocysteine 0.791 0.767, 0.815 0.014 ACC_2006_8_VascularDisease.indd 357 1/4/06 5:21:28 PM 358A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n Conclusions Better CVD risk prediction is obtained when all the components of the MS are included as continuous variables rather than a categorical diagnosis of the MS. This supports the hypothesis that the increased risk in the MS may be the combined effect of its components. A small but statistically signiﬁcant improvement in CVD risk prediction is obtained by incorporating white cell count and homocysteine. 9:30 a.m. 842-5 Microalbuminuria Is Associated With Severe Angiographic Coronary Artery Disease in Diabetics and Non-Diabetics Rishi Sukhija, Wilbert S. Aronow, Priyanka Kakar, Rajesh Sachdeva, Luis Garza, Anjan K. Sinha, Jawahar L. Mehta, University of Arkansas for Medical Sciences, Little Rock, AR, New York Medical College, Valhalla, NY Background: Microalbuminuria is a well known risk factor for coronary artery disease (CAD) in diabetics as well as non-diabetics. It is associated with higher cardiovascular mortality, especially in diabetics. Microalbuminuria appears to be a signal from the kidneys that the vasculature, particularly the endothelium, is not functioning normally. However, there are no data linking angiographic severity of CAD to microalbuminuria. Methods: We examined coronary angiograms for the extent of severe CAD (luminal narrowing ≥50%) in the following four groups; group A: patients with type 2 diabetes mellitus (DM) and microalbuminuria (n=54); group B: patients with DM but no microalbuminuria (n=54); group C: patients without DM but with microalbuminuria (n=47); and group D: patients without DM and without microalbuminuria (n=47). Results: The mean age of patients in groups A, B, C, and D was 71 ± 7 years, 71 ± 6 years, 71 ± 7 years, and 72± 7 years, respectively (p-not signiﬁcant). Gender distribution in the 4 groups was also not signiﬁcantly different. There was no signiﬁcant difference in the prevalence of hypertension, hypercholesterolemia, and current smoking between the four groups. Three-vessel CAD was present in 40 of 54 (74%) group A patients, in 23 of 54 (43%) group B patients, in 18 of 47 (38%) group C patients, and in 10 of 47 (21%) group D patients (p <0.001 comparing group A with group B, group A with group C, and group A with group D; p <0.025 comparing group B with group D). Two- or three-vessel CAD was present in 50 of 54 (93%) group A patients, in 37 of 54 (69%) group B patients, in 35 of 47 (74%) group C patients, and in 21 of 47 (45%) group D patients (p< 0.001 comparing group A with group D; p < 0.005 comparing group A with group B, and group C with group D; p <0.02 comparing group A with group C and group B with group D). Conclusions: Patients with microalbuminuria have more severe angiographic CAD than those without microalbuminuria. This relationship is independent of other risk factors, and is particularly evident in patients with DM. Therefore, patients with microalbuminuria, especially those with DM, may need screening and more aggressive treatment for CAD. 9:45 a.m. 842-6 Waist Circumference and Body Mass Index Are Both Independently Associated With Cardiovascular Disease. The International Day for the Evaluation of Abdominal Obesity (IDEA) Survey Steve Haffner, Jean-Pierre Despres, Beverley Balkau, John E. Deanﬁeld, Philip Barter, Jean-Pierre Bassand, Keith Fox, Luc Van Gaal, Hans-Ulrich Wittchen, Chee E. Tan, Sidney C. Smith, University of Texas Health Science Centre, San Antonio, TX Background: IDEA is an international non-interventional cross-sectional study which aims to describe the prevalence of abdominal obesity (measured by waist circumference) and associated risk factors in 157,211 patients (41% men), 18 to 80 years, consulting 6,060 primary care physicians (PCPs) on a given day in 63 countries over 5 continents. Methods: Demographic data, waist circumference (WC), body mass index (BMI), and presence of a cardiovascular disease (CVD) - coronary heart disease, stroke, revascularisation - were collected by the PCPs. This analysis aims to determine relationship between presence of CVD, WC and BMI. The odds ratios (ORs) and 95% conﬁdence intervals (95%CI) were estimated from multiple logistic regression models, separately for men and women, after adjustment for marked differences in geographic regions. The ORs are for an increase in 1 SD in each of the variables. Results: Variables in model (SD men/women) OR [95%CI] For CVD Men Women Model 1 Age (16/16 years) 3.42 [3.32;3.53]* 3.30 [3.21;3.40] * BMI (5.0/5.9 kg/m2) 1.32 [1.29;1.35]* 1.37 [1.34;1.40] * Model 2 Age (16/16 years) 3.30 [3.20;3.40]* 3.16 [3.07;3.25] * WC (14/15 cm) 1.36 [1.33;1.40]* 1.40 [1.36;1.43] * Model 3 Age (16/16 years) 3.34 [3.24;3.44]* 3.21 [3.12;3.30] * BMI (5.0/5.9 kg/m2) 1.13 [1.09;1.17]* 1.19 [1.15;1.23] * WC (14/15 cm) 1.24 [1.19;1.29]* 1.22 [1.18;1.26] * *: p<0.0001 In both men and women, WC and BMI were independently associated with the presence of CVD. Conclusions: The IDEA survey provides evidence that waist circumference is associated with cardiovascular disease independently of BMI and of age, and indicates its importance in cardiovascular disease even after adjusting for age. 10:00 a.m. 842-7 Clusters of Cardiovascular Risk Factors: A Health Economics Perspective for the Metabolic Syndrome Leonardo Tamariz, Ana Palacio, Bill West, Therese Burdey, Hermes Florez, University of Miami - Humana Health Services Research, Miami, FL Background: Several reports have questioned the value of clustering cardiovascular (CV) risk factors as metabolic syndrome (MS) to predict adverse outcomes. We evaluated the hypothesis that MS increases health care (medical and pharmacy) costs. Methods: We analyzed retrospective claims data from a large health beneﬁts company to identify 401,013 individuals with at least one risk factor for coronary artery disease (CAD) using ICD-9 codes for hypertension, diabetes, lipid abnormalities, and obesity. MS equivalent was deﬁned based on the presence of three or more of these CV risk factors. We added total health care costs for 12 months after the identiﬁcation of the cardiovascular risk factor and used generalized linear models. Results: The mean annual health care costs increased with the number of CV risk factors both in those with and without CAD (Table) and this trend remained signiﬁcant after adjusting for gender and age (p<0.01). The same signiﬁcant trend was seen for medical and pharmacy costs. The adjusted total annual health care cost in those with an isolated CV risk factor was USD 3780.3 (95% C.I.: 3743 - 3818) while in those with MS equivalent was USD 6022.5 (95% C.I.: 5967 - 6078). Conclusions: Health care costs are higher in individuals with MS equivalent regardless of age, gender and CAD status. Metabolic syndrome and its components may have an important economic impact on the health care system. Total health care costs by numbers of CV risk factors in those with and without CAD Number of risk factors CAD No CAD Number Mean Cost (SD) Number Mean Cost (SD) 1 28536 12788.2 (23287.1) 154651 4654.2 (12274.1) 2 35496 16939.1 (29744.9) 122150 6523.4 (15279) 3 15522 21242.5 (35533.1) 39280 8149.5 (18967.3) 4 1681 30315.5 (45839.4) 3697 13596.6 (36813.6) 10:15 a.m. 842-8 Effect of Bariatric Surgery on Cardiovascular Risk Factors and Predicted Effect on Cardiovascular Events and Mortality in Class II-III Obesity John A. Batsis, Abel Romero-Corral, Maria L. Collazo-Clavell, Michael G. Sarr, Virend Somers, Lee Brekke, Francisco Lopez-Jimenez, Mayo Clinic College of Medicine, Rochester, MN, Brekke Associates Inc., Minneapolis, MN Background:Obesity is a major cardiovascular (CV) risk factor. Bariatric surgery (BS) is an approved therapeutic alternative for obesity class II-III. There are no population-based, controlled studies assessing the effect of BS on long-term CV risk or estimatations of prevented adverse outcomes. Methods:We performed a population-based, longitudinal, and historical study between 1990-2003, of 197 consecutive patients from Olmsted County, MN, with class II-III obesity treated with Roux-en-Y gastric bypass and 163 control patients assessed in a weight reduction program. We used the observed change in CV risk factors and risk models derived from NHANES I and NHEFS data to calculate the predicted impact on CV events and mortality for the surgical and control groups. Results:Mean follow-up was 3.3 years. Risk factor changes are presented in the table. The baseline estimated 10-year risk for CV events was 37.1% for the surgical group and 30.2% for controls, which changed at follow-up to 18.3% and 30.0% respectively. Risk modeling to predict 10-year outcomes estimated 16.2 CV events and 4.1 overall deaths prevented by BS per 100 patients compared to the control group. The number needed to treat (NNT) to prevent one CV event with BS was 6, for CV death was 33, and for death of any cause was 24. Risk Factor Surgery Control Baseline (n=197) Follow-up (n=197) Baseline (n=163) Follow-up (n=163) Age, years 44.0 (10.0) - 43.3 (10.9) - Female Sex 158 (80.8%) - 119 (73.0%) - Body Mass Index, mg/kg2 49.4 (8.9) 34.0 (8.1) 43.9 (5.7) 43.7 (7.7) Systolic BP, mmHg 133.5 (15.4) 121.2 (16.1) 133.1 (18.1) 127.8 (16.1) Diastolic BP, mmHg 79.5 (9.7) 71.8 (11.2) 76.7 (10.5) 75.5 (10.3) Cholesterol, mg/dL 198.9 (38.2) 153.6 (32.2) 208.0 (40.7) 193.3 (41.5) HDL- Cholesterol, mg/dL 45.3 (11.2) 54.9 (15) 44.6 (13.5) 48.8 (12.5) LDL- Cholesterol, mg/dL 117.1 (32.1) 76.9 (24.2) 121.2 (35.4) 108.7 (32.9) Fasting blood glucose, mg/dL 117.5 (36.7) 94.9 (21.3) 120.2 (35.4) 117.0 (44.3) Meeting criteria for diabetes 59 (30.0%) 19 (11.0%) 41 (24.8%) 45 (32.8%) Ever Smoker 21 (12%) - 26(19%) BP= Blood pressure. Numbers are reported as mean ± standard deviations in brackets, except when noted as otherwise ACC_2006_8_VascularDisease.indd 358 1/4/06 5:21:28 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 359A Vascular D isease, H ypertension, and P revention Conclusions:BS induces a considerable and long-lasting improvement in cardiovascular risk factors in patients with obesity class II-III. Improvement in CV risk predicts a signiﬁcant, 10-year reduction in CV events and deaths. ORAL CONTRIBUTIONS 845 Effects of Lipid and Blood Pressure- Lowering on Inﬂammation and Atherosclerosis Tuesday, March 14, 2006, 11:00 a.m.-12:30 p.m. Georgia World Congress Center, Room B313 11:00 a.m. 845-3 Inﬂammatory Activation During Coronary By-pass Surgery and the Effect of High Dose Statin Plus ACE- inhibitor Treatment Alberto Radaelli, Claudia Loardi, Elena Negro Cusa, Danilo Santo, Lorenzo Menicanti, Giovanni Paolini, Maria Luisa Lavitrano, Alberto U. Ferrari, Prevention & Health Biotech, Univ Milano-Bicocca, Monza, Italy, Divisione Riabilitazione Cardiologica, Osp. San Gerardo, Monza, Italy Background: On-pump coronary (CABG) surgery triggers a potentially noxious inﬂammatory response (InﬂResp). Purpose: to characterize the time course of InﬂResp in both systemic and coronary blood; ii) to determine whether pretreatment with a statin/ ACE-inhibitor association can inhibit the InﬂResp. Methods: patients undergoing elective CABG surgery (n=21) were randomized (< 15 days before CABG) to standard (STD, ramipril 2.5 mg plus simvastatin 20 mg or atorvastatin 10 mg) or high dose (HiDo, ramipril 10 mg plus simvastatin 80 mg or atorvastatin 40 mg) daily treatment. Plasma interleukin 6 (IL6, pg.ml-1), tumour necrosis factor-α (TNF-α, pg.ml-1) and E-selectin were assayed (ELISA) pre- and post- (10 as well as 60 min) on- pump circulation. Blood samples were simultaneously obtained from a systemic vein, a radial artery and the coronary sinus. Results: In the STD group (n=10), both IL6 and TNF-α (but not E-selectin) displayed a signiﬁcant increase which was similar at all sites and peaked between 10 and 60 min post pump. The increase was drastically attenuated in the HiDo group (n=12). The main results are shown in Table (mean±ESM, * p<0.02 vs before; ^ p<0.02 vs STD; 60 min data not shown). Conclusions: On-pump CABG surgery is associated with a striking inﬂammatory response as documented by increased circulating levels of IL6 and TNF-α. The response can be almost completely prevented by an ACE-inhibitor/statin association provided the treatment is started well in advance and high drug doses are employed Pre/post pump IL6 STD IL6 HiDo TNF STD TNF HiDo Pre Artery 0,3±0,2 1,2±0,6 1,7±1,1 1,0±0,8 Pre Vein 0,3±0,2 1,2±0,6 2,7±1,5 1,7±1,0 Pre Coro Sin 0,9±0,3 2,6±0,2 4,4±2,5 3,3±1,6 Post Artery 32,4±10.2* 7,6±2,0* 41,0±17*^ 1,9±0,9^ Post Vein 41±10* 7,4±2,3^ 43,7±19* 2,0±1,1^ Post Coro Sin 36,2±12* 7,5±1,2*^ 46,1±17* 1,7±0,8^ 11:15 a.m. 845-4 Additive Beneﬁcial Effects of Fenoﬁbrate Combined with Candesartan in the Treatment of Hypertriglyceridemic, Hypertensive Patients Kwang K. Koh, Michael J. Quon, Seung Hwan Han, Eak Kyun Shin, Gachon Medical School, Incheon, South Korea, Diabetes Unit, NIH, Bethesda, MD Background: Biological mechanisms underlying ﬁbric acid (PPARa ligand) and angiotensin II type 1 receptor blocker therapies differ. Experimental studies demonstrated cross-talking between PPARa and RAS system. We investigated vascular and metabolic responses to these therapies either alone or in combination in hypertriglyceridemic, hypertensive patients. Methods: This was a randomized, double-blind, placebo-controlled cross-over trial with three treatment arms (each 2 months) and two washout periods (each 2 months). Forty-four patients were given fenoﬁbrate 200 mg and placebo, fenoﬁbrate 200 mg and candesartan 16 mg, or candesartan 16 mg and placebo daily during each 2 month treatment period. Results: Fenoﬁbrate, combined therapy, or candesartan signiﬁcantly reduced systolic and diastolic blood pressure after 2 months administration compared with baseline. However, combined therapy signiﬁcantly reduced blood pressure more than fenoﬁbrate or candesartan alone (P<0.001 by ANOVA). When compared with candesartan, fenoﬁbrate or combined therapy signiﬁcantly improved the lipoprotein proﬁle. All three treatment arms signiﬁcantly improved ﬂow-mediated dilator response to hyperemia. Combined therapy signiﬁcantly decreased plasma malondialdehyde (MDA), hsCRP, and soluble CD40L levels relative to baseline measurements. Importantly, these parameters were changed to a greater extent with combined therapy when compared with monotherapy (P<0.001, P=0.002, P=0.050, and P=0.032 by ANOVA, respectively). Fenoﬁbrate, combined therapy, and candesartan signiﬁcantly increased plasma adiponectin levels and insulin sensitivity (determined by QUICKI) relative to baseline measurements. However, the magnitude of these increases were not signiﬁcantly different among three therapies (P=0.246 and P=0.153 by ANOVA, respectively). Conclusions: Fenoﬁbrate combined with candesartan improves endothelial function and reduces inﬂammatory markers to a greater extent than monotherapy with either drug in hypertriglyceridemic, hypertensive patients. 11:30 a.m. 845-5 Losartan Combined With Simvastatin Shows Additive Beneﬁcial Effects on Inﬂammation in the Treatment of Hypercholesterolemic, Hypertensive Patients Kwang K. Koh, Seung Hwan Han, Gachon Medical School, Incheon, South Korea Background: Biological mechanisms underlying statin and angiotensin II type 1 receptor blocker therapies differ. Experimental studies demonstrated cross-talking between LDL cholesterol and RAS system. We investigated vascular responses to these therapies either alone or in combination in hypercholesterolemic, hypertensive patients. Methods: This was a randomized, double-blind, placebo-controlled cross-over trial with three treatment arms (each 2 months) and two washout periods (each 2 months). Forty- seven hypertensive, hypercholesterolemic patients were given simvastatin 20 mg and placebo, simvastatin 20 mg and losartan 100 mg, or losartan 100 mg and placebo daily during each 2 month treatment period. Results: Losartan alone or combined therapy signiﬁcantly reduced blood pressure when compared with simvastatin alone. When compared with losartan alone, simvastatin alone or combined therapy signiﬁcantly changed lipoproteins. All three treatment arms signiﬁcantly improved ﬂow-mediated dilator response to hyperemia and decreased plasma malondialdehyde (MDA) and MCP-1 levels relative to baseline measurements. However, these parameters were changed to a greater extent with combined therapy when compared with simvastatin or losartan alone (both P<0.001 and P=0.030 for MCP-1 by ANOVA). Simvastatin alone did not signiﬁcantly reduce soluble CD40 ligand (sCD40L) levels relative to baseline measurements, however, simvastatin signiﬁcantly reduced sCD40L levels from 4.25±0.33 to 2.84±0.33 ng/mL (P=0.004) in patients with high baseline sCD40L >2.0 ng/mL. Combined therapy or losartan alone signiﬁcantly decreased the plasma sCD40L levels relative to baseline measurements by 14±7% (P=0.001) and 13±10% (P=0.001), respectively. These decreases were signiﬁcantly greater than those observed with simvastatin alone (P=0.023 by ANOVA). Conclusions: Simvastatin combined with losartan improves endothelial function and reduces inﬂammatory markers to a greater extent than monotherapy with either drug in hypercholesterolemic, hypertensive patients. 11:45 a.m. 845-6 The Anti-Proliferative Effect on Vascular Smooth Muscle Cells by Rosiglitazone Is Mediated by Inhibition of the Akt-mTOR-p70S6K Pathway Sungha Park, Woo-Chul Chang, Jin-Bae Kim, Hee Sang Song, Young-Guk Ko, Donghoon Choi, Ki-Chul Hwang, Yangsoo Jang, NamSik Chung, Yonsei University College of Medicine Cardiovascular Center, Seoul, South Korea Background: Thiazolidinediones are known to inhibit vascular smooth muscle cell(VSMC) proliferation by reducing mitogen induced degradation of p27Kip1 resulting in increased activity of Retinoblastoma protein(RB). However, the upstream signaling mechanisms associated with the above mentioned mechanism has not been elucidated. The mammalian Target of Rapamycin(mTOR) is a key regulatory kinase that plays a major role in the mammalian cell cycle, and the Rapamycin eluting stents have proven to signiﬁcantly reduce the rate of coronary stent restenosis. In this study, we hypothesize that Rosiglitazone, a PPAR-γ agonist, inhibits VSMC proliferation through the inhibition of Akt-mTOR-p70S6 kinase pathway. Method: Rat aortic VSMCs were prepared from thoracic aorta of 200-250g male Sprague- Dawley rats. The cells were treated with PPAR-� ligand rosiglitazone 10 µM added 24 hours before the addition of mitogenic stimulus such as insulin(1 µM), recombinant platelet-derived growth factor (PDGF)-BB (10ng/ml), and H2O2(0.5mM). Cell proliferation was measured using the thiazolyl blue tetrazolium bromide (MTT) colorimetric assay. Western blot analysis and RT PCR was performed to determine whether inhibition of the Akt and mTOR signaling pathway by Rosiglitazone is associated with subsequent antiproliferative response. Results: VSMC proliferation was signiﬁcantly inhibited in cells treated with Rosiglitazone. Western blot analysis demonstrated signiﬁcant inhibition of expression of Akt, phosphorylated-Akt, m-TOR, phosphorylated m-TOR, p70S6K and phosphorylated p70S6K in cells treated with rosiglitazone, demonstrating the inhibition of the expression and activation of the Akt-mTOR-p70S6K pathway by Rosiglitazone. This inhibitory effect was increased with increasing concentration of Rosiglitazone. RT-PCR revealed signiﬁcantly decreased transcripts of Akt, m-TOR and p70S6k in cells treated with rosiglitazone. Conclusion: The inhibitory effect of rosiglitazone on VSMC proliferation in vitro is mediated by the inhibition of Akt-m-TOR-p70S6K pathway. Further studies to demonstrate the inhibition of this pathway in vivo is needed. Noon 845-7 Early Comprehensive Characterisation of the Vascular Response to Statin Treatment Using MRI Justin Lee, Cheerag Shirodaria, Jane Francis, Clare Jackson, Matthew Robson, Stefan Neubauer, Keith Channon, Robin Choudhury, Frank Wiesmann, University of Oxford, Oxford, United Kingdom Background: MRI allows accurate, serial non-invasive imaging. Statins rapidly improve vascular function; reduction in atherosclerosis is often observed after >6 months (m). We hypothesised that functional improvement precedes & predicts plaque regression. ACC_2006_8_VascularDisease.indd 359 1/4/06 5:21:29 PM 360A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n Methods: 34 newly diagnosed CAD patients imaged at 1.5T before, 3 & 12m after starting a statin. Aortic distensibility & brachial artery ﬂow mediated dilatation (FMD) & glyceryl trinitrate (NTG) response were measured with trueFISP cine. Transverse black blood turbo spin echo images of descending thoracic aorta were also acquired. Results: Mean total cholesterol was 202 ±8 mg/dL at baseline, 151 ±6 mg/dL & 152 ±6 mg/dL at 3 & 12m. Mean aortic wall cross sectional area was reduced after only 3m - by 2.5% & by 5.4% at 12m (Fig.1a); lumen area was unchanged (p=NS). Importantly, reductions at 3m correlated with those at 12m, (r=0.77 p<0.001). Signiﬁcant (p<0.05) increases in distensibility of ascending (AA), proximal descending (PD) and distal descending (DD) aorta seen after 3m (& 12m) of 39% (46%), 37% (58%) and 28% (72%) (Fig.1b). Mean FMD improved from 8.1% to 12.8% & 13.7% at 3 & 12M (p<0.003 both). NTG response did not change (p=NS). Conclusion: 1) MRI detects reduction in atherosclerosis after only 3m on statins: the earliest structural changes reported to date. 2) Structural and functional assessment permits more precise characterisation of disease and response to treatment. 12:15 p.m. 845-8 Nicotinic Acid-Induced Vasodilation in Mice Is Predominantly Mediated via the Prostagladin D2 Receptor 1 Tsuei-Ju Wu, Kenneth K. Wu, Claudio Sturino, Zhaoyin Wang, Gary O’Neill, Samuel D. Wright, Gerard Waters, Kang Cheng, Merck Research Laboratories, Rahway, NJ, Merck Frosst Canada, Kirkland, PQ, Canada Background: Nicotinic acid is a drug commonly used to treat dyslipidemia, but it also elicits the adverse effect of ﬂushing, which is comprised of cutaneous vasodilation with associated discomfort. Methods: An animal model of nicotinic acid-induced ﬂushing has been established in C57BL/6 mice using a laser Doppler perfusion imager to scan the ventral side of mouse ear for blood ﬂow. Results: As in humans, nicotinic acid stimulated vasodilation in the mouse ear in a dose- dependent manner, was associated with an increase of the vasodilatory prostaglandin D2 (PGD2) in plasma and could be blocked by pretreatment with aspirin. Nicotinic acid- induced vasodilation could also be inhibited by a cyclooxygenase I (COX I)-selective inhibitor, but not by a cyclooxygenase II (COX-II)-selective inhibitor. Two PGD2 receptors have been identiﬁed, PGD2 receptor 1 (DP1) and PGD2 receptor 2 (DP2). DP2 does not mediate nicotinic acid-induced vasodilation as the DP2-speciﬁc agonist DK-PGD2 did not induce cutaneous vasodilation, and DP2-/- mice had a normal vasodilatory response to nicotinic acid. By contrast, BW245C, a DP1-selective agonist, induced vasodilation in mice, and MK-0524, a DP1-selective antagonist, blocked both PGD2- and nicotinic acid- induced vasodilation. Nicotinic acid-induced vasodilation was also studied in DP1+/+, DP1+/- and DP1-/- mice. Although nicotinic acid-induced vasodilation was completely dependent on DP1 in female mice, it was only partially dependent on DP1 in male mice. Conclusion: In the mouse, DP1 appears to be an important component involved in niaicn-induced vasodilation, but DP1-independent mechanisms also may to be involved. These studies suggest that DP1 receptor antagonism may be an effective means to suppress nicotinic acid-induced ﬂushing in humans. ORAL CONTRIBUTIONS 848 Hypertension: Risk Stratiﬁcation Tuesday, March 14, 2006, 11:00 a.m.-12:30 p.m. Georgia World Congress Center, Room B407 11:00 a.m. 848-3 Metabolic Syndrome Predicts Higher Cardiovascular Risk Independently of ECG Left Ventricular Hypertrophy: The LIFE Study Giovanni de Simone, Michael H. Olsen, Kristian Wachtell, Darcy A. Hille, Bjorn Dahlof, Hans Ibsen, Sverre E. Kjeldsen, Paulette A. Lyle, Richard B. Devereux, Federico II University Hospital, Naples, Italy Background: Metabolic syndrome (MetS) is a phenotype with high cardiovascular (CV) risk. Relation of MetS with CV outcome might be less evident when preclinical CV disease is present. We explored whether MetS is associated with increased CV risk in hypertensive patients (pts) with established target organ damage (ECG left ventricular hypertrophy [LVH]) in the LIFE study. Methods: MetS was deﬁned as the presence of at least 2 risk factors in addition to hypertension: body mass index (BMI) ≥30 kg/m2, HDL-cholesterol (HDL-C) <40/50 mg/ dL (men/women), glucose ≥110 fasting or ≥140 mg/dL nonfasting or diabetes (DM). CV death and primary composite endpoint (CEP) of CV death, stroke, and myocardial infarction were examined with adjustment for age, sex, severity of ECG LVH, diabetes, and prevalent CV disease. Results: Among 8494 pts with available data, 1467 met requirements for MetS (17%; 894 women [61%]), including 685 pts with DM. Among pts with MetS, prevalence of low HDL-C was as high (73%) as prevalence of obesity (79%). Baseline CV disease was similarly prevalent in pts with (29%) or without (24%) MetS. Pts with MetS had higher pulse pressure (2.8 mmHg), serum creatinine (0.06 mg/dL), and Cornell product (2.3 units), but lower Sokolow-Lyon voltage (3.0 units) than those without MetS (all p<0.0001). CEP was more frequent in the presence than in the absence of MetS (HR=1.29, 95% CI 1.11-1.50), independently of confounders. Similarly, the risk of CV death was higher in MetS (HR 1.60, 1.27-2.00). In the LIFE study, losartan was more effective than atenolol in reducing CV risk in hypertensive pts, and this subgroup analysis shows that the treatment effect does not vary in patients with MetS (HR 0.86, 0.66-1.13) or without MetS (HR 0.86, 0.75-0.99) (interaction not signiﬁcant). Conclusions: MetS is associated with higher CV event rates in hypertensive pts already exhibiting target organ damage, independently of diabetes. Losartan is more effective than atenolol in reducing CV risk in pts with or without MetS. 11:15 a.m. 848-4 Regression of Electrocardiographic Left Ventricular Hypertrophy by Both Cornell Voltage-Duration Product and Sokolow-Lyon Voltage During Antihypertensive Therapy is Associated With Decreased Incidence of Sudden Cardiac Death: The LIFE Study Peter M. Okin, Richard B. Devereux, Katherine E. Harris, Sverker Jern, Sverre E. Kjeldsen, Jonathan M. Edelman, Björn Dahlöf, for the LIFE Study Investigators, Cornell Medical Center, New York, NY Background:Although the presence and severity of ECG left ventricular hypertrophy (LVH) have been associated with an increased risk of sudden cardiac death (SCD), whether regression of ECG LVH during antihypertensive therapy is associated with a decreased incidence of SCD has not been examined. Methods:ECG LVH was evaluated over time in 9193 hypertensive patients enrolled in the LIFE study. Patients were treated with losartan- or atenolol-based regimens and followed with serial ECGs at 6 months and then yearly until death or study end. ECG LVH was measured using gender-adjusted Cornell product (CP; (RaVL+SV3 [+6 mm in women])*QRS duration) and Sokolow-Lyon voltage (SLV; SV1+RV5/6). SCD was deﬁned as death due to coronary heart disease occurring within 24 hours of symptom onset. Results: After mean follow-up of 4.8±0.9 years, SCD occurred in 90 patients (1.0%). In time-dependent Cox analyses controlling for treatment effects, regression of ECG LVH by SLV and CP were associated with a decreased risk of SCD: every 1SD decrease in SLV (10.5 mm) was associated with a 33% lower incidence (HR 0.67, 95% CI 0.56-0.81) and every 1 SD decrease in CP (1050 mm•msec) with a 28% lower incidence of SCD (HR 0.72, 95% CI 0.63-0.81). After adjusting for treatment, Framingham risk score, baseline and in-treatment systolic and diastolic pressure, both in-treatment SLV and CP retained predictive power when included in the same multivariate Cox model: every 1SD decrease in SLV was associated with a 44% lower incidence (HR 0.56, 95% CI 0.42-0.75) and every 1 SD decrease in CP with a 19% lower incidence of SCD (HR 0.81, 95% CI 0.67- 0.98). In this model, a 1 SD decrease in both SLV and CP was associated with a 54 % decreased risk of SCD (HR 0.46, 95% CI 0.28-0.73) after controlling for risk factors. Conclusions:Regression of ECG LVH by SLV and CP during antihypertensive therapy is associated with a decreased likelihood of SCD, independent of blood pressure lowering and treatment modality in essential hypertension, with regression of ECG LVH by both criteria associated with the lowest risk. These ﬁndings suggest that antihypertensive therapy targeted at regression or prevention of ECG LVH by CP and SLV criteria may reduce the incidence of SCD. ACC_2006_8_VascularDisease.indd 360 1/4/06 5:21:29 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 361A Vascular D isease, H ypertension, and P revention 11:30 a.m. 848-5 High Hemoglobin was Associated With Cardiovascular Events, Low Hemoglobin With All-Cause Mortality, and Large Fall in Hemoglobin With Both in Patients With Hypertension and Left Vetricular Hypertrophy. The LIFE Study Michael H. Olsen, Kristian Wachtell, Gareth Beevers, Björn Dahlöf, Richard B. Devereux, Ulf de Faire, Frej Fyhrquist, Hans Ibsen, Sverre E. Kjeldsen, Ole Lederballe-Pedersen, Lars H. Lindholm, Markku S. Nieminen, Per Omvik, Suzanne Oparil, Hans Wedel, Glostrup University Hospital, Glostrup, Denmark Background: Although hemoglobin (Hb) is a cardiovascular (CV) risk marker in the general population, recent research in patients with kidney disease suggests that erythropoiesis-stimulating agents might improve outcome. Therefore, we wanted to investigate the prognostic importance of baseline Hb and changes in Hb and test whether treatment with losartan versus atenolol had any inﬂuence on Hb and its prognostic value in the LIFE study. Methods: Hb was measured at baseline and annually during losartan- or atenolol-based treatment in 9193 hypertensive patients with left ventricular (LV) hypertrophy. Endpoints were all-cause and non-CV mortality and a CV composite endpoint (CEP) of CV death, non-fatal stroke, or non-fatal myocardial infarction. Results: Hb was reduced signiﬁcantly more in patients treated with losartan versus atenolol (142 to 137 mg/dl vs. 142 to 140 mg/dl, P<0.001). Plotting event rates in deciles of baseline Hb and changes in Hb showed U-shaped curves. Therefore, we compared the event rate in the upper and lower deciles with the middle 80%. CEP was independently predicted by high baseline Hb (hazard ratio (HR)=1.33 per mg/dl, P<0.05), large fall in Hb (HR=1.53 per mg/dl, P<0.001), and atenolol-based treatment (HR=1.23, P<0.01), whereas CV mortality was independently predicted by low baseline Hb (HR=1.55 per mg/dl, P<0.05) and large fall in Hb (HR=2.07 per mg/dl, P<0.001). Non-CV mortality and all-cause mortality were independently predicted by low baseline Hb (HR=1.69 per mg/dl, P<0.05 and 1.64 per mg/dl, P<0.01), large fall in Hb (HR=2.33 and HR=2.25 per mg/ dl, both P<0.001), and large increase in Hb (HR=1.55 per mg/dl, P<0.05 and HR=1.43 per mg/dl, P<0.01). Large increase in Hb was only associated with non-CV mortality (HR=1.83 per mg/dl, P<0.05) and all-cause mortality (HR=1.60 per mg/dl, P<0.01) in patients receiving atenolol-based antihypertensive treatment. Conclusions: Although losartan-based antihypertensive treatment was associated with a more pronounced reduction in Hb, high baseline Hb and large fall predicted CEP, whereas low baseline Hb, large fall, and large increase in Hb predicted all-cause mortality independently of treatment. 11:45 a.m. 848-6 Prevalence, Treatment, and Control of Hypertension in U.S. Adults 2001-2002 Overall and With Metabolic Syndrome, Diabetes, Kidney Disease, Stroke or Coronary Artery Disease Nathan D. Wong, Victor A. Lopez, Stanley S. Franklin, Sue Ellen Kline, Gilbert L’Italien, Roland Chen, University of California, Irvine, Irvine, CA, Bristol Myers-Squibb, Princeton, NJ Background: Hypertension (HTN) is a major contributor to cardiovascular disease (CVD) risk, especially in high risk individuals. We examined the prevalence, treatment, and control of HTN in U.S. adults in the National Health and Nutrition Examination Survey 2001-2002, overall, and among those with the metabolic syndrome, diabetes, kidney disease, stroke, peripheral arterial disease (PAD) and cardiovascular disease. Methods: HTN was deﬁned as a systolic blood pressure (BP) of >140 mmHg or diastolic BP of >90 mmHg, or >130/80 mmHg if diabetes or kidney disease were present, or reported use of medication for HTN. PAD was deﬁned by an ankle-brachial index <0.9. Results: The table below presents the prevalence of HTN, and of those with HTN, treatment and control rates (to below HTN cutpoints) weighted to the U.S. population, overall, and by disease condition: Group (weighted n, in millions [M]) Prevalence of HTN Proportion Treated for HTN Proportion Controlled for HTN Overall (196.5 M) 30.7% 60.9% 43.4% Metabolic Syndrome (31.9 M) 57.8% 67% 42.1% Diabetes (14.0 M) 75.5% 70.6% 24.5% Kidney Disease (9.5 M) 80.6% 65.5% 19.9% Stroke (4.2 M) 69% 79% 27.6% Heart Failure (7.8 M) 70.3% 83.3% 45.5% Peripheral Arterial Disease (5.2 M) 75.1% 74% 28.9% Coronary Artery Disease (9.0 M) 71.9% 84.6% 49.2% More than two-thirds of persons with diabetes, stroke, kidney disease, peripheral arterial disease, and CVD have HTN. In spite of greater treatment rates than in the general population, control rates are especially low in those with diabetes (25%), kidney disease (20%), stroke (28%), or PAD (29%). Multiple logistic regression showed metabolic syndrome (odds=0.34, 95% CI=0.26-0.45) and stroke (odds=0.33, 95% CI=0.16-0.71) to be independently associated with a lower likelihood of BP control. Conclusions: Improved efforts to reach target blood pressure levels are needed, in particular for high risk groups where control remains poor. Noon 848-7 Adverse Cardiovascular Outcomes With Atenolol in Clinical Trials in Hypertension: An Updated Meta- Analysis William J. Elliott, Rush Medical College, Chicago, IL Background: A recent meta-analysis of clinical trials that included atenolol as a ﬁrst- line antihypertensive drug indicated that death, cardiovascular death, and stroke were signiﬁcantly more common in those randomized initially to atenolol. Methods: The numbers of patients at risk for, and those experiencing, cardiovascular events were abstracted from the 5 studies included in the previous meta-analysis. These were added to similar data from the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints, International VErapamil/trandolapril STudy, and Anglo- Scandinavian Cardiac Outcomes Trials. All were subjected to meta-analysis using the traditional Mantel-Haenszel technique. Results: The numbers of affected and at-risk patients in each group, summary odds ratios (OR), 95% conﬁdence interval (CI), and P-value for homogeneity (P [homo]) for death, cardiovascular (CV) death, myocardial infarction (MI), and stroke are shown in the table below. Endpoint Atenololn of N Other n of N Summary OR (95% CI) P (homo) Death 2596 of34,202 2390 of 34,161 1.10 (1.03-1.16) P = 0.003 0.25 CV Death 1228 of32,598 1097 of 32,562 1.13 (1.04-1.22) (P = 0.005) 0.04 MI 1277 of32,598 1338 of 32,562 1.05 (0.97-1.14) P = 0.19 0.06 Stroke 1079 of32,598 864 of 32,562 1.26 (1.15-1.38) P = 0.0000006 0.71 Conclusions: Even when all currently-available clinical trial data are included, atenolol had a signiﬁcantly higher risk of all-cause mortality and stroke than other antihypertensive therapy. The previous warning about the use of atenolol as initial treatment for hypertension appears to still be warranted. 12:15 p.m. 848-8 Effects of Amlodipine or Enalapril Versus Placebo on Rates of Cardiovascular Hospitalization and Costs Among Coronary Artery Disease Patients With Normal Blood Pressure: Findings From the CAMELOT Economic Substudy Joe Menzin, Luke Boulanger, Simon Tang, Kamlesh M. Thakker, Steven E. Nissen, Boston Health Economics, Inc., Waltham, MA, Cleveland Clinic Foundation, Cleveland, OH Background: Administration of amlodipine reduced adverse cardiovascular (CV) events versus placebo in patients with coronary artery disease (CAD) and normal blood pressure in the CAMELOT study. We assessed the effects of amlodipine besylate (A) 10 mg daily or enalapril maleate (E) 20 mg daily versus placebo on CV-related hospitalization and costs of CV care over 2 years among patients in the CAMELOT study. Methods: A prospective economic study was conducted by analyzing CV-related hospitalizations, study drugs, concomitant CV drugs from CAMELOT, and cost data from external sources, expressed in 2004 US dollars. Hospitalizations were categorized by CV diagnoses (angina, myocardial infarction, chronic heart failure, stroke/TIA, new PVD) and revascularization procedures (PTCA ± coronary stent, CABG) performed. The daily cost of inpatient care was estimated by type of CV hospitalization using data from the Hospital Cost and Utilization Project database, and assigned to observed days of inpatient care. Inpatient physician costs were based on the Medicare payments, while average wholesale prices for medications (based on generic products, if available) were from the Redbook. The proportion of patients with 1+ CV hospitalizations was evaluated. Mean values and 95% conﬁdence intervals (CIs) were estimated for cost data. Results: 1991 patients were randomized to study treatment (663 A, 673 E, and 655 placebo). The mean age was 58 years, and approximately 75% were males. 16.4% of A patients had 1+ CV hospitalizations during follow-up compared with 22.7% for placebo (P<0.01) and 20.1% for E (P=0.09). The mean 2-year per-patient cost of CV care was $8,261 for A, $8,863 for placebo, and $8,967 for E. Mean costs were estimated to be lower for A versus placebo (-$602; 95% CI: -$2,386 to $1,219) or E (-$707; 95% CI: -$2,414 to $988). Conclusions: This economic analysis suggests that patients with established CAD and apparently normal blood pressure, treated with A had a statistically signiﬁcantly lower likelihood of CV hospitalization than those randomized to placebo. Moreover, it is reasonably likely that A was associated with lower costs of CV care. ACC_2006_8_VascularDisease.indd 361 1/4/06 5:21:30 PM 362A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n ORAL CONTRIBUTIONS 849 Treatment Issues in Prevention Tuesday, March 14, 2006, 11:00 a.m.-12:30 p.m. Georgia World Congress Center, Room B312 11:00 a.m. 849-3 Improvement of Metabolic Parameters with Rimonabant Beyond the Effect Attributable to Weight Loss Alone: Pooled 1-Year Data from the RIO (Rimonabant In Obesity and Related Metabolic Disorders) Program Xavier Pi-Sunyer, Jean-Pierre Despres, Andre Scheen, Luc Van Gaal, Columbia University College of Physicians and Surgeons, New York, NY Background: Preclinical data show that rimonabant acts peripherally to increase adiponectin production (adipose tissue) and glucose uptake (muscle), and decrease lipogenesis (adipose tissue and liver). In four RIO trials (n=6,625), rimonabant reduced body weight and waist circumference, improved multiple cardiometabolic parameters, and was generally well tolerated. Methods: Based on preclinical evidence of the direct peripheral effect of rimonabant, prespeciﬁed analyses were used to assess the relationship between body weight and metabolic effect with respect to HDL-cholesterol (HDL-C), TG (triglycerides), HbA1c, and fasting insulin; exploratory analyses included adiponectin. The differences between rimonabant 20 mg and placebo treatment that could not be attributed to weight loss alone were assessed using standard regression methodology, in which weight loss (change from baseline to 1 year) was introduced as a covariate (analysis of covariance, ANCOVA). Results: After adjustment for body weight loss, rimonabant 20 mg signiﬁcantly increased HDL-C and adiponectin, and reduced TG (Table). Signiﬁcant improvements beyond those attributed to body weight loss were also seen for HbA1c in type 2 diabetic patients and fasting insulin in non-diabetic patients. Rimonabant 20 mg Cardiometabolic parameter Overall effect (mean difference vs placebo at 1 year) Effect beyond that of body weight loss alone (mean difference vs placebo at 1 year) % of overall effect beyond that of body weight loss alone HDL-C (%) 8.0 (0.6)p<0.001 3.6 (0.6) p<0.001 45% TG (%) -14.0 (1.4)p<0.001 -6.5 (1.4) p<0.001 46% Fasting insulin (µIU/ml) -2.74 (0.48)p<0.001 -1.34 (0.51) p=0.018 49% Adiponectin (µg/ml) 1.5 (0.2) p<0.001 0.85 (0.21) p<0.001 57% HbA1c (%) -0.67 (0.07)p<0.001 -0.37 (0.07) p<0.001 55% HDL-C, TG: RIO-Lipids, RIO-Diabetes, RIO-Europe and RIO-North America; HbA1c: RIO-Diabetes; Adiponectin: RIO-Lipids; Fasting insulin: RIO-North America, RIO- Europe and RIO-Lipids. Results are presented as mean (SEM) Conclusions: Rimonabant therapy improved multiple cardiometabolic parameters to a greater degree than could be attributed to body weight loss alone, possibly reﬂecting the metabolic effects of rimonabant in peripheral tissues. 11:15 a.m. 849-4 Characteristics Predicting Successful Weight Reduction in Overweight and Obese Post Infarction Patients Yazid Y. Fadl, Harlan M. Krumholz, Mikhail Kosiborod, Frederick A. Masoudi, Pamela N. Peterson, Kimberly J. Reid, William S. Weintraub, John A. Spertus, Cardiovascular Outcomes Research Consortium, Kansas City, MO Background: In light of the growing epidemic of obesity, national guidelines recommend weight loss to improve cardiovascular risk. Among patients recovering from a myocardial infarction (MI), it is not known what factors are associated with successful weight loss. Methods: A total of 1,677 MI patients were prospectively enrolled in the 19-center PREMIER study and followed for 1 year. Weight categories based on patients’ 1-month reported weight were assigned as follows: overweight (BMI=25-29.9), obese (BMI=30- 39.9), and morbidly obese (BMI≥40). Percent weight loss was determined from the difference between the 1-month and 1 year patient-reported weight. A multivariable linear regression model was used to determine predictors of percent weight loss. Results: 1,253 (75%) of patients followed for 1 year were overweight or heavier at baseline and formed the denominator for this study. The median change in weight (as a percentage of total body weight) at 1 year is as follows: 0% for overweight, 0.4% loss for obese and 1.2% loss for morbidly obese. Multivariable analysis results are shown in the Table. Conclusion: In overweight MI patients, characteristics independently associated with higher rates of weight loss include the absence of depression, being non-diabetic, morbidly obese, older, currently smoking, and having multiple ofﬁce visits to the cardiologist. Awareness of these characteristics may help to identify and facilitate patients’ weight loss goals. Variable Name* Estimate 95% C.I. p-value Morbidly Obese vs. Overweight 5.1% greater weight loss 3.0 - 7.2 <0.0001 Morbidly Obese vs. Obese 3.7% greater weight loss 1.6 - 5.8 0.0005 Smokers vs. Quitters 2.9% greater weight loss 1.3 - 4.4 0.0002 Non-depressed vs. depressed 2.1% greater weight loss 0.6 - 3.5 0.006 Non-diabetics vs. Diabetics 1.0% greater weight loss 0.0 - 2.1 0.05 Age (in 1-year increments) 0.1% greater weight loss 0.0 - 0.1 0.0003 # of Cardiologist Ofﬁce Visits 0.5% greater weight loss 0.0 - 1.0 0.04 *Predictors forced into the model included: patients’ weight category at 1 month (overweight [BMI=25-29.9], obese [BMI=30-39.9], and morbidly obese [BMI≥40]), age, sex, race, presence of depression, level of education, heart failure, diabetes, dyslipidemia, smoking status, social support, SF-12 physical component score, discharge diet instructions, and the number of cardiac rehab, cardiologist and internist ofﬁce visits 11:30 a.m. 849-5 Impact of Triglyceride Lowering on HDL-c: Is There a Continuum of HDL-c Increase Beyond Fasting TG < 150 mg/dl? Michael Miller, Patricia Langenberg, Stephen Havas, University of Maryland Medical Center, Baltimore, MD Background: While an inverse association between triglycerides (TGs) and high-density lipoprotein cholesterol (HDL-c) is well documented, the impact of TG lowering on HDL-c raising has not been well established. Methods: Data were analyzed in 159 patients with CHD or CHD risk factors who made multiple clinic visits (n=1,201) to a University Preventive Cardiology Center between 1991-2005. Following baseline evaluation, various therapies were employed (i.e., dietary, exercise, medication) to reduce mean LDL (143 mg/dL) and TG (281 mg/dL). Results: At follow-up, fasting TG levels were divided into NCEP categories as deﬁned: “desirable” (TG < 150), “borderline-high” (TG 150-199), “high” (TG 200-499) and “very high” (TG > 500). Mean HDL-c levels attained within each NCEP TG category is shown in the Table and demonstrates signiﬁcantly higher HDL-c at successively lower TG cutpoints. When “desirable” TG < 150 was then divided into <100 (n=277) and 100-149 (n=258), signiﬁcant increases in HDL-c persisted in the lowest TG group (50.7 vs 43.7) (P < 0.0001). Conclusions: These data support a continuum of HDL-c elevation in conjunction with TG reductions that are maintained well below desirable NCEP TG cutpoints. If higher HDL-c lowers CHD risk, then the present study raises the possibility that lower TGs (i.e., < 100) may be more advantageous than TG < 150 as part of an overall CHD risk reducing strategy. {6819C76C-990F-4882-A61B-28824E015C4B}$$ 11:45 a.m. 849-6 Atrial Fibrillation: Bridging of Chronically Anticoagulated Patients With Low Molecular Weight Heparin Prior to Interventional Procedures: Experience in 455 Patients From the Brave-registry Christoph Hammerstingl, Gerlinde Schlang, Christina Platen, Harald Schmidt, Kyung Mi Jeong, Heyder Omran, St. Marien Hospital Bonn, Bonn, Germany Background: It is recommended to discontinue oral anticoagulation (OAC) in chronically anticoagulated patients (pts) with atrial ﬁbrillation (AF) and concomittant thromboembolic (TE) risk factors prior to interventions with high risk of bleeding. To prevent TE complications, pts should receive weight adapted bridging therapy with unfractioned heparin intravenously. LMWH have a higher bioavailability and more predictive anticoagulatory effect, therefore, effective anticoagulant therapy can be achieved by subcutaneous application of LMWH. We recommend TE-risk adjusted dosage of LMWH in pts with AF. The aim of this registry was to assess the safety and practicability of bridging therapy with LMWH in TE-risk adapted dosage. Methods: Chronically anticoagulated pts with AF and indication for interruption of OAC were included in the registry. Pts at high TE-risk (AF and age > 75 y; Age < 75y and several concomitant risk factors; LAA thrombus and/or dense spontaneous echocontrast; history of thromboembolism; chronic heart failure) received weight adapted enoxaparin s.c. twice a day (0,1mg/kgBW/12h). The remaining patients (n = 131) recieved enoxaparin in half therapeutic dosage. Procedures were performed at INR<1.5. After procedure OAC was reintroduced under LMWH therapy until effective INR was reachieved. All pts were followed up regarding bleeding complications, occurence of clinical signs of thromboembolism and other adverse events under LMWH-therapy. Results: 455 pts were treated with enoxaparin, 324 with AF at high thromboembolic risk, 131 pts at intermediate thromboembolic risk. Age 73.3±10.5 y; mean treatment time 7.2±5.1 d; 44 pts underwent major surgery, 411 minor surgery or other interventions with high risk of bleeding. In 19 pts occured minor bleeding, 0 major bleeding. No thromboembolic complication evolved due to bridging therapy. Conclusions: Bridging therapy with low molecular weight heparin (enoxaparin) is safe and feasible in a large cohort of patients with atrial ﬁbrillation. We recommand dose adjusted treatment according to the individual thromboembolic risk. ACC_2006_8_VascularDisease.indd 362 1/4/06 5:21:30 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 363A Vascular D isease, H ypertension, and P revention Noon 849-7 Obesity Increases the Risk of Conversion of Paroxysmal to Chronic Atrial Fibrillation: Data From a 21-Year Community-Based Study Marion E. Barnes, Yoko Miyasaka, Stephen S. Cha, Kent R. Bailey, Walter P. Abhayaratna, Bernard J. Gersh, James B. Seward, Teresa S.M. Tsang, Mayo Clinic, Rochester, MN Background: Obesity has been proposed as a risk factor for atrial ﬁbrillation (AF) development. Whether obesity increases the risk of conversion from paroxysmal (PAF) to chronic atrial ﬁbrillation (CAF) is unknown. Methods: Residents of Olmsted County, MN, with electrocardiogram (ECG)-documented AF between 1980-2000 were identiﬁed, and followed in the medical records to 2004. This study population consisted of the subgroup of patients whose ﬁrst AF was classiﬁed as PAF. Cox proportional hazards modeling was used to determine the risk factors for conversion to CAF. Results: Of 4,618 individuals (mean ± SD age 73 + 14 years, 51% men) diagnosed with ﬁrst AF, AF presentation was classiﬁed as PAF in 3428 subjects (mean age 72 ± 15 years; men 68, women 76 years). Of these, 568 (17%) converted to CAF over a follow up period of 5.3 ± 5.5 years. BMI was strongly predictive of conversion to CAF. The age- and sex- adjusted hazard ratio (HR) comparing the highest (≥ 30.0 kg/m2) to lowest (< 23 kg/m2) BMI quartile was 1.66 (95% CI, 1.37-2.01; p<0.0001). After multiple adjustments (Table), obesity remained a signiﬁcant independent predictor of conversion from PAF to CAF. Conclusions: BMI was independently predictive of progression from PAF to CAF. Patients with incident PAF and BMI ≥ 30 had a 1.66-fold increase in risk for CAF development. This data may have important implications for the management of obesity and AF. Variable Hazard Ratio 95% CI Pr>ChiSq Age 1.029 1.021-1.038 <0.0001 BMI ≥30 1.432 1.192-1.720 0.0001 Diastolic blood pressure 1.009 1.001-1.018 0.0369 Valvular heart disease 1.566 1.260-1.946 <0.0001 History or concurrent CHF 1.284 1.025-1.610 0.0300 Hypertension 1.322 1.024-1.707 0.0320 Smoking history 1.316 1.093-1.585 0.0038 Digoxin 1.556 1.351-1.791 <0.0001 Heart rate at AF, concurrent MI, history of cardiac surgery, and calcium channel blocker use were all negatively predictive of conversion from PAF to CAF (all p<0.05) 12:15 p.m. 849-8 Risk of Hemorrhagic Stroke in Atrial Fibrillation: Is There an Ethnic Difference in Its Incidence and in the Effect of Warfarin? Albert Y-J Shen, Janis F. Yao, Wansu Chen, Michael B. Jorgensen, Somjot S. Brar, Kaiser Permanente Medical Center, Los Angeles, CA Background Treatment with warfarin reduces atrial ﬁbrillation (AF) related ischemic stroke at a cost of a slight excess of hemorrhagic stroke. We assessed whether there is an ethnic difference in hemorrhagic stroke incidence and in the effect of warfarin. Methods We identiﬁed all ﬁrst time hospitalizations for non-rheumatic AF in patients without prior or acute stroke from 1995 to 2000 for all 2 million plus Southern California Kaiser adult members. Average follow-up was 3.3 years. Warfarin usage was obtained from pharmacy records, while AF, type of stroke, and other co-morbidities were based on hospital discharge ICD-9 codes. We recorded the event rate of each ethnicity while on or not on warfarin. Results We identiﬁed 20,835 AF hospitalizations, of which 15,860 (76%) were Caucasian, 1,650 (8%) were AA, 1,952 (9.4%) were Hispanics and 786 (3.8%) were Asians. There were 196 hemorrhagic stroke events. Treatment with warfarin did not signiﬁcantly increase hemorrhagic stroke risk in the entire cohort or in any ethnic group. After adjusting for age, gender, warfarin use, hypertension, diabetes, and heart failure, the hazard ratio for hemorrhagic stroke with Caucasians as referent is shown. Warfarin Users Warfarin Nonusers # of Hemorrhagic Strokes / Person-Years 42 / 15560 154 / 53118 Hemorrhagic Stroke/100 Person- Years Risk Ratio (95% CI) All 0.27 0.29 0.93 (0.66 - 1.31) Caucasian 0.24 0.24 1 (0.67 - 1.53) AA 0.24 0.45 0.53 (0.16 - 1.79) Hispanic 0.34 0.44 0.77 (0.30 - 2.04) Asian 0.73 0.58 1.26 (0.45 - 3.53) Adjusted Hazard Ratio 95% CI Caucasian 1 AA 1.97 1.23 - 3.15 Hispanic 2.24 1.48 - 3.40 Asian 3.43 2.08 - 5.66 Conclusions In a large, multiethnic cohort of AF patients, the hemorrhagic stroke rate was low for all ethnicities whether or not on warfarin. After adjustment for stroke risk factors and warfarin use, AA, Hispanics and Asians were at successively greater hemorrhagic stroke risk than Caucasians. POSTER SESSION 1023 Platelets, Thrombosis, and Fibrinolysis Tuesday, March 14, 2006, 12:30 p.m.-4:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 12:30 p.m.-1:30 p.m. 1023-159 A Study of Platelet Function Following Selective and Combined Blockage of the ADP P2Y1 and P2Y12 Receptors Benoit Labarthe, Catherine Martel, Jacynthe Rivard, Marta Ghitescu, Pierre Theroux, Montreal Heart Institute, Montreal, PQ, Canada Background: The study aims to characterize the effects on human platelets of blocking the P2Y1 receptors involved in initiating aggregation, the P2Y12 receptors which maintain aggregation and the two receptors concomitantly. MRS2179 (MRS) and clopidogrel (Clop) served as selective blockers for P2Y1 and P2Y12, respectively. Methods. Blood was obtained on antithrombins from 10 patients using aspirin for stable coronary artery disease before and 24 hours after a single oral dose of Clop (450 mg). MRS (100µM) was added ex vivo. Peak and late aggregation (AGG) to ADP 2.5 and TRAP 2.5 µM was measured. Platelet activation (ACT) was assessed by ﬂowcytometry for CD62P, PAC-1, and monocyte- and neutrophil-platelet conjugates. Results (Table). Clop and MRS alone inhibited AGG and ACT to both agonists, MRS being more efﬁcient for inhibiting ADP effects than Clop. With TRAP, the two drugs produced similar inhibition of AGG but Clop blocked ACT more effectively. Dual receptors inhibition almost completely blocked ADP effects; synergism was found on AGG to TRAP, but MRS added little to Clop on ACT. Conclusion. The data stress a potential importance of P2Y1 in mediating ADP effects, and suggest differential effects of the two receptors on TRAP. Dual receptors inhibition nearly completely inhibits ADP effects while facilitating inhibition of AGG to TRAP. ADP 2.5µM TRAP 2.5µM % inhibition to baseline MRS 100µM Clop 450mg MRS + Clop MRS 100µM Clop 450mg MRS + Clop Aggmax 91 (86-92)0.074 27 (14-48) 0.074 93 (86-95) 12 (8-23) 0.139 14 (2-18) 0.047 27 (18-43) Agg6min 87 (74-96)0.327 67 (50-100) 0.050 95 (84-100) 21 (9-52) 0.878 30 (12-63) 0.022 83 (36-100) P-selectin 86 (82-91)0.009 74 (65-79) 0.005 97 (93-99) 18 (2-30) 0.203 32 (-7-68) 0.646 38 (1-44) PAC-1 66 (51-79)0.059 50 (35-68) 0.005 93 (84-95) 20 (13-44) 0.139 65 (7-77) 0.139 64 (50-79) Mono/Plt 80 (70-84)0.066 64 (4-71) 0.005 87 (78-92) 9 (-17-33) 0.139 24 (9-45) 0.262 31 (5-56) PMN/Plt 68 (65-77)0.241 61 (34-76) 0.013 76 (72-89) 11 (-9-24) 0.285 18 (-17-58) 0.646 34 (-15-65) p-values compare values within cells to value in the cell next to the right. Values are medians and 25th and 75th percentile. Aggmax: maximal aggregation; Agg6min: late aggregation; Mono/Plt: platelet/monocyte conjugates; PMN/Plt.neutrophil/platelet conjugates 1023-160 Prevalence and Platelet Function Proﬁles of Clopidogrel Hypo-responders Identiﬁed Following Drug Withdrawal Esther Bernardo, Dominick J. Angiolillo, Celia Ramirez, Manel Sabate, Pilar Jimenez- Quevedo, Cecilia Corros, Alfonso Suarez, Fernando Alfonso, Marco A. Costa, Theodore A. Bass, Antonio Fernandez-Ortiz, Carlos Macaya, University of Florida-Shands Jacksonville, Jacksonville, FL, San Carlos University Hospital, Madrid, Spain Background: Individuals variably respond to treatment with clopidogrel (C). Hypo- responders (HR) to C have been deﬁned as individuals with a <10% “decrease” in platelet reactivity following C administration. However, if HR to C may be alternatively identiﬁed as those in whom C withdrawal is associated with a <10% “increase” in platelet reactivity has still not been explored. Since diabetics are more likely to be HR to antiplatelet therapy, we considered a diabetic population to test our hypothesis. Methods: Platelet function was assessed in 82 diabetics while on combined aspirin (100 mg/d) + C (75mg/d) therapy (T1) and one-month following C withdrawal (T2). HR and non-HR to C were deﬁned as patients with a <10% or >10% increase in 20µM ADP-induced platelet aggregation (PA). PA was also assessed following 6µM ADP and 6µg/mL collagen stimuli. Results: A total of 22 patients (27%) patients were HR to C. At T1, HR had higher PA compared to non-HR (Table; p<0.01 for all assays). PA proﬁles were similar in HR at T1 and T2. Conversely, in non-HR patients C withdrawal was associated with a rebound increase in all PA values (T1 vs T2, p<0.001) which were markedly higher compared to PA values in HR. Platelet aggregation proﬁles ADP 20µΜ ADP 6µΜ collagen 6µg/mL T1 T2 T1 T2 T1 T2 HR 62.9±9.7 61.9±9.6 54.0±13.4 58.3±12.6 50.7±18.2 48.3±15.5 Non-HR 50.1±11.1 75.1±9.8 39.4±12.5 66.4±12.1 39.5±16.7 54.2±17.9 ACC_2006_8_VascularDisease.indd 363 1/4/06 5:21:31 PM 364A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n Conclusions: A considerable number of patients may be idenitifed as HR to C based on the degree of PA following drug withdrawal, in whom combination of C with aspirin is not associated with synergistic antiplatelet effects. Alternative antiplatelet regimens are warranted in these patients to achieve more enhanced platelet inhibition. 1023-161 The Active Metabolite of Prasugrel (CS-747) Inhibits ADP-Stimulated Thrombo-inﬂammatory Markers of Platelet Activation: Modulation by Other Blood Cells and Calcium, But Not by Aspirin Andrew L. Frelinger, III, Joseph A. Jakubowski, YouFu Li, Marc R. Barnard, Marsha L. Fox, Matthew D. Linden, Atsuhiro Sugidachi, Kenneth J. Winters, Mark I. Furman, Alan D. Michelson, University of Massachusetts Medical School, Worcester, MA, Eli Lilly and Company, Indianapolis, IN Background: The thienopyridine prodrug prasugrel (CS-747/LY640315), a platelet P2Y12 ADP receptor antagonist, requires in vivo metabolism for activity. Here we used prasugrel’s active metabolite, R-138727, to directly evaluate the kinetics and dose- dependence of its P2Y12 inhibitory activity in vitro as reported by ADP-stimulated platelet thromboinﬂammatory responses. Methods: Blood (PPACK and citrate anticoagulated) from 9 healthy donors pre- and post- aspirin (ASA) was incubated with R-138727 and the response to ADP (20 µM) assessed by aggregometry and by ﬂow cytometric analysis of leukocyte-platelet aggregates, platelet surface P-selectin, and GPIIb-IIIa activation (reported by the activation-dependent antibody PAC1). Using the time required to achieve steady-state inhibition (30 min), the IC50 of R-138727 for each marker was evaluated in whole blood and PRP. Results: R-138727 produced rapid (steady-state inhibition at 15-30 min), potent (complete inhibition of whole blood aggregation at 1 µM R-138727), and consistent (coefﬁcient of variation 6%) inhibition of these endpoints in PPACK-anticoagulated whole blood, while inhibition was slower in citrate-anticoagulated blood. Prior ASA ingestion did not alter the kinetics. ADP-stimulated whole blood aggregation was more sensitive to inhibition by R- 138727 (IC50 0.23±0.04 µM) than all other assays including PRP aggregation (IC50 >3.6±0.6 µM) and was unaffected by ASA ingestion. Similarly, R-138727 inhibited ADP-stimulated platelet P-selectin expression more potently in whole blood than in PRP suggesting a role for blood cell-derived nucleotidases. IC50s were generally lower in PPACK than in citrate. Only ADP-stimulated GPIIb-IIIa activation and platelet surface expression of P-selectin were reduced by prior ingestion of ASA, and these effects were small. Conclusions: R-138727, the active metabolite of prasugrel, produces rapid, potent and consistent inhibition of ADP-stimulated thromboinﬂammatory markers of platelet activation - clinically advantageous characteristics for an antiplatelet agent. This inhibition is modulated by other blood cells and calcium but, as tested, is largely unaffected by aspirin. 1023-162 Prevalence of Concomitant Suboptimal Responsiveness to Aspirin and Clopidogrel Treatment in Diabetic Patients Esther Bernardo, Dominick J. Angiolillo, Celia Ramirez, Manel Sabate, Pilar Jimenez- Quevedo, Fernando Alfonso, Cecilia Corros, Alfonso Suarez, Marco A. Costa, Theodore A. Bass, Antonio Fernandez-Ortiz, Carlos Macaya, University of Florida-Shands Jacksonville, Jacksonville, FL, San Carlos University Hospital, Madrid, Spain Background: The prevalence of suboptimal responders (SR) to either aspirin (ASA) or clopidogrel (C) is increased in diabetic (D) patients (pts). However, the prevalence of SR concomitantly to both drugs in D pts is unknown. Aim of the study: to assess the prevalence of ASA+C-SR and how this inﬂuences platelet biomarkers in D pts. Methods: Platelet function was assessed in 187 D with stable coronary artery disease on long-term ASA (100 mg/d) + C (75mg/d) therapy. ASA-SR was deﬁned by the PFA-100 analyzer using collagen/epinephrine coated cartridges (closure times <193 seconds); C- SR was deﬁned using the upper quartile value of 20µM ADP-induced platelet aggregation (PA). Platelet biomarkers also included: a) PA (expressed as percentage of maximal PA) following 6µM ADP, 6µg/ml collagen, 25µM TRAP and 20µM epinephrine stimuli; b) whole blood ﬂow cytometry assessment of ADP-induced platelet activation (expressed as percentage of positive platelets): GPIIb/IIIa activation (anti-ﬁbrinogen binding, AFB) and P-selectin expression (CD62P-PE binding). Results: In the overall population, 51% and 25% of pts were ASA- and C- SR, respectively. Thirteen percent of pts were concomitantly ASA+C-SR, in whom all platelet biomarkers resulted increased (Table). PA ADP 6µM (%) PA ADP 20µM (%) PA collagen(%) PA TRAP (%) PA epinephrine(%) AFB (%) P-selectin (%) ASA+C-SR n=25 54.9±38.9 69.4±5.6 59.9±12.5 73.4±7.9 43.0±15.2 40.2±17.7 45.0±16.0 Non ASA+C- SR n=162 38.9±14.3 49.6±13.4 40.4±18.1 67.6±14.5 30.6±15 29.6±19.3 28.8±16.9 p-value <0.001 <0.001 <0.001 <0.005 <0.001 0.01 <0.001 Conclusions: A considerable number of D pts are SR concomitantly to both ASA and C. SR to ASA+C is associated with markedly increased platelet reactivity setting these pts at an enhanced ischemic risk. 1023-163 Increased Platelet-Leukocyte Aggregation in Indian Asian Men: A Mechanism Contributing to Greater Cardiovasular Risk? Jehangir N. Din, Olivia A. Ashman, Rachel A. Archer, Jaydeep Sarma, Alasdair W. Jubb, Syed M. Aftab, David E. Newby, Andrew D. Flapan, Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, United Kingdom, Royal Inﬁrmary of Edinburgh, Edinburgh, United Kingdom Background: CHD mortality is strikingly higher in Indian Asians compared with European Caucasians. This is not explained by differences in traditional cardiovascular risk factors. Platelet-leukocyte aggregates are sensitive markers of platelet activation and contribute to the initiation and progression of atherothrombosis. We investigated whether healthy Indian Asians had increased platelet activation compared with Caucasians. Methods: We recruited 25 healthy Indian Asian and European Caucasian men. Venous blood was drawn for ﬂow cytometric analysis. Platelet-monocyte and platelet-neutrophil aggregates were deﬁned as monocytes and neutrophils positive for CD42a respectively. P-selectin on platelets was deﬁned as platelets positive for CD62P. Soluble P-selectin and soluble CD40 ligand were measured with ELISA. Results: Indian Asians had increased platelet-monocyte aggregates (38.3±2.9% vs. 22.7±1.2%, p<0.0001) and platelet-neutrophil aggregates (9.4±0.9% vs. 6.4±0.5%, p=0.005) compared with Caucasians. There was no difference in platelet P-selectin expression, soluble P-selectin or soluble CD40 ligand. Conclusions: We have demonstrated increased platelet-leukocyte aggregates in healthy Indian Asian men. This may represent an important and previously unreported mechanism contributing to their increased cardiac risk. Studies are warranted to determine whether earlier or more aggressive anti-platelet therapy can improve outcomes in this high-risk population. 1023-164 The Role of Platelet Activity in Patients With Patent Versus Occluded Coronary Artery Bypass Grafts. Prague-4 Trial Subanalysis Pavel P. Osmancik, Heidi Mocikova, Frantisek Bednar, Petr Stros, Petr Widimsky, Cardiocenter, 3rd Medical School Charles University, Prague, Czech Republic Background: Platelets play a key role in acute coronary syndromes as well as in atherosclerosis progression. We tested the hypothesis, whether platelet activity could be associated with bypass graft closure. Methods: Eighty patients from Prague-4 study were examined retrospectively according to their graft patency. Group A consisted of forty patients with the lowest patency rate from the study, each patient had at least one occluded graft at one-year coronary angiogram (total graft count: 109, patency rate: 37%). Group B consited of forty controls, i.e. patients with all patent grafts(total graft count:97, patency rate 100%). Both groups were similar with respect to age, gender, smoking status, diabetes, hypertension, ejection fraction of left ventricle, medication and basal laboratory parameters, both groups were operated by the same surgeons. Platelet activity was determined by membrane expression of platelet antigen CD41 (part of GpIIb/IIIa integrin), CD42 (von Wilebrand factor receptor) and CD 62P (P-selectin) by ﬂow cytometry as mean ﬂuorescence intensity (CD41, 42b) or % of positive cells (CD62P). Platelet aggregability was measured by ADP-aggregometry. Results: Membrane expression of platelet antigens CD41, CD42b and CD62P were similar in both groups (CD41: 11.8+2.4(A) vs. 12.3+2.3 (B), p=n.s.; CD42b:12.6+1,5(A) vs. 12.7+1.9(B), p=n.s.; CD62P: 1,5+1,7%(A) vs. 1.13+1.4%(B), p=n.s. (Wilcoxon test). Platelet aggregability was also similar between both groups (52.1+15.6%(A) vs. 56.1+16.3%(B), p=n.s., Wilcoxon test). Signiﬁcant correlation was found between CD41, CD42b expression and glycemia (r=0.6, p<0.001), CD62P and triglycerides (r=0.5, p<0.05, both Spearman test). Conclusions: Although higher glycemia and lipid levels are associated with higher platelet activity, higher platelet activity is not associated with lower graft patency in patients after coronary artery bypass surgery. Platelets seem not to play key role in the graft closure. 1023-165 Reduced Platelet Sensitivity to Aspirin in Type 2 Diabetic Subjects Compared to Non-Diabetics FM Pulcinelli, Luigi Biasucci, Simona Giubilato, Andrea Leo, S. Riondino, S. Di Renzo, E. Triﬁrò, T. Mattiello, D. Pitocco, G. Liuzzo, G. Ghirlanda, F. Crea, Catholic University, Rome, Italy, La Sapienza University, Rome, Italy Background: Recent studies have shown that aspirin (ASA) is less effective in prevention of cardiovascular disease in diabetic subjects compared with non diabetic subjects. Therefore, we sought to evaluate the presence of a reduced platelet sensitivity to ASA in type 2 diabetes. Methods: We compared 42 type 2 diabetic subjects with 53 non diabetic subjects; all subjects were receiving ASA (for >7 days), but no other antiplatelet agents. Platelet activation was determined with platelet aggregation method, considering maximal percentage of aggregation (Mx%) in response to: ADP , arachidonic acid (AA) and ACC_2006_8_VascularDisease.indd 364 1/4/06 5:21:32 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 365A Vascular D isease, H ypertension, and P revention Mx% and lag phase in response to collagen. In vitro collagen-induced platelet TXA2 production was measured in platelet untreated and treated with ASA and/or a COX-2 inhibitor (NS-398).Platelet COX-2 presence was assessed with western-blot analysis using an anti COX-2 MoAb in 10 diabetics and 10 non dibetic patients. Results: platelet aggregation was signiﬁcantly higher in diabetic compared with control subjects both in response to both AA (Mx% 16% ± 4 vs 7% ±1, p=.05) and collagen (Mx% 54% ± 5 vs 41% ±4, p=0,05; lag phase 54’’±4 vs 92’’±6,p=.001). The enhanced platelet response to ADP in diabetic subjects was not statistically signiﬁcant (Mx% 40% ± 2 vs 30% ±2, p= NS). Collagen-induced TXA2 levels were signiﬁcantly higher in diabetic subjects than in controls (1015±280 vs 123 ± 40, p=.006). In vitro treatment with ASA resulted in a signiﬁcant decrease in TXA2 levels (51.4 ±12 vs 1015 ± 280,p=.001) in diabetics only. A further reduction in TXA2 was obtained combining ASA with NS-398 (31±10 vs 51,4 ± 12, p=.02).Detectable amount of COX-2 werefound in platelets from all diabetics and only in 2/10 non-diabetics Conclusions: our study demonstrates that diabetic patients are less sensitive to antiplatelet action of ASA compared with non diabetics as revealed by enhanced platelet aggregation and by higher TXA2 levels. Our data also suggest that the higher levels of TXA2 are due to residual platelet COX 1 activity and, to a lesser extent, to the presence of platelets COX-2 activity 1023-166 Antiplatelet Effects of Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin II Subtype 1 Receptor Blockers (ARBs): Modiﬁed Ex Vivo Platelet Aggregation of 374 Cardiovascular Patients Achim Viktor, Dirk Skowasch, Anne Floeck, Gerhard Bauriedel, University of Bonn, Bonn, Germany Background: ACE inhibitors and ARBs are cornerstones in medical treatment of cardiovascular patients. They have shown signiﬁcant risk reduction in myocardial infarction, stroke and mortality in several randomised, double-blind and placebo-controlled trials. Based on the concept of antithrombotic effects of ACE inhibitors and ARBs, the present study evaluates the coagulative ex vivo activity in cardiovascular patients (CV) with ACE inhibitors and ARBs and compares these data with in those from untreated patients and with those from patients treated with established antithrombotics such as aspirin (ASA) or clopidogrel/aspirin. Methods: Blood samples from 374 patients with coronary heart disease and/or arterial hypertension were analyzed by whole-blood lumi-aggregometry. Platelet aggregation was determined by the increase in impedance across paired electrodes in response to the stimulatory agents collagen and adenosine diphosphate (ADP), respectively. Results: As the central ﬁnding, ex vivo platelet aggregation was attenuated by ACE inhibitors, ARBs and aspirin or clopidogrel/aspirin, indicated by a lower increase in impedance compared with that of untreated patients. After ADP induction, platelet aggregation decreased by 37% with ACE inhibitors (P=0.003), by 39 % with ARBs (P=0.011), by 39% with ASA (P=0.007) and by 82% with ASA/clopidogrel (P=0.011). Following collagen induction, platelet aggregation decreased by 23% with ACE inhibitors (P<0.001), by 34% with ARBs (P<0.001), by 36% with ASA (P<0.001); with ASA/ clopidogrel there was a trend to inhibition (27%; P=0.23). Conclusions: The present ex vivo data on whole-blood aggregometry provide direct evidence that ACE inhibitors and ARBs decrease platelet aggregation, while aspirin and clopidogrel are conﬁrmed as established antithrombotics. Pleiotropic effects of ACE inhibitors and ARBs on platelet function may contribute to the clinical beneﬁt observed for these drug classes in cardiovascular end points trials. 1023-167 Effects of Aggrenox and Telmisartan Versus Clopidogrel and Aspirin in Combination on Platelet Activity in Diabetic Patients: An ex vivo Outlook to the PRoFESS Trial Victor Serebruany, Alex Malinin, Wendy Ziai, Alex Pokov, Deepak L. Bhatt, Mark Alberts, Dan Hanley, HeartDrug Research, Towson, MD Background: Chronic use of antiplatelet agents improve morbidity, mortality, and reduce the incidence of second stroke. Aggrenox (Ag) + telmisartan (T), or clopidogrel (C) + aspirin (ASA) in combination are currently being tested in a large trial (PRoFESS). We determined ex vivo changes of platelet biomarkers over time after these treatments in diabetic cohort. Methods: Blood samples from 40 patients who were treated with Ag (twice daily)+T (80mg) or C (75mg)+ASA (325mg) were analyzed. All patients received ASA for at least one month prior to enrollment. Platelets were assessed at baseline, Day 15, and Day 30. Results: There were no differences in the baseline characteristics between groups. C+ASA provided fast and sustained inhibition of ADP-induced (p=0.0003), and later collagen-induced (p=0.002) aggregation. Expression of PECAM-1 (p=0.02) and formation of platelet-leukocyte microparticles (p=0.01) were also signiﬁcantly reduced early in the C+ASA treated patients. In contrast, Ag+T therapy has been associated with the delayed reduction of GP IIb/IIIa activity (p=0.04), GP Ib (p=0.002), vitronectin receptor (p=001), P-selectin (p=0.007), LAMP-1 (p=0.009), CD40-ligand (p=0.02), PAR-1 intact (p=0.01) and cleaved (p=0.01) thrombin receptor expression which was either not found in C+ASA or not to the same extent as in the Ag+T treated patients. GP IIb/IIIa antigen and CD63 were not affected by both regimens. Conclusion: Ex vivo proﬁle of platelet biomarkers was entirely different in patients treated with Ag+T versus C+ASA. While C+ASA showed stronger and faster response of functional platelet tests, the Ag+T regimen produced delayed, signiﬁcant downregulation of multiple major activation-dependent platelet receptors, which was not typical for C+ASA treated patients. Chronic beneﬁt of T and Ag beyond inhibition of platelet aggregation may well be due to complimentary effects yielding additional clinical beneﬁt in long term treatments as tested in PRoFESS. 1023-168 Late- Acquired Incomplete Apposition After Drug- eluting Stents: Frequency and Potencial for Late Stent Thrombosis Dimytri A. Siqueira, Alexandre Abizaid, Fausto Feres, Luiz A. Mattos, Rodolfo Staico, Julio Maia, Luiz F. Tanajura, Andrea S. Abizaid, Aurea J. Chaves, Amanda G.M.R. Sousa, Gary S. Mintz, J.Eduardo Sousa, Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil, Cardiovascular Research Foundation, New York, NY Background: Late-acquired incomplete stent apposition ( ISA ) have been documented after drug-eluting stent (DES) implantation; however, frequency and long-term clinical outcomes of patients (pts) who presented with ISA remains controversial. We sought to investigate the frequency and clinical consequences of late-acquired ISA after implantation of sirolimus-eluting stents (SES) or paclitaxel-eluting stents (PES) in a non- selected population. Methods: From our clinical and core intravascular ultrasound (IVUS) laboratory databases, 195 patients who underwent DES placement (175 pts with SES and 20 pts with PES) into native artery lesions had serial IVUS performed ( at index procedure and after 6-months). Late ( 6months ) ISA was deﬁned as separation of at least 1 stent strut from the vessel wall in a segment without a side-branch and where the immediate post- implantation IVUS revealed complete apposition of stent struts. Results: We identiﬁed 10 pts with late-acquired ISA ( 5,1%) , 3 pts after PES and 7 pts after SES. Late ISA was localized almost exclusively at mid-portion of the stents ( 9/10 ). Mean ISA area and length was 5,64 ± 0,61 mm2 and 4,19 ± 2,12 mm, respectively. There was an increase in vessel volume (416,01 ± 163,93 to 514,43 ± 247,91 mm3) with no change in plaque volume ( 212,40 ± 52,74 to 219,26 ± 110,83 mm3 ) in patients who presented with this vascular abnormality. After 19 ± 9 months of follow -up, 1 patient with SES and 1 with PES who presented with ISA had late stent thrombosis ( 1152 and 331 days after stent implantation, respectively ), manifested as acute myocardial infarction. Conclusions: Late-acquired ISA was observed in 5,1% of pts after DES implantation. Although uncommon, late-acquired ISA could be one of the mechanisms related to adverse clinical events at long-term follow-up. 1023-169 Should Anticoagulation Be Used During Routine Diagnostic Coronary Angiography? Anwar Tandar, Christopher M. Lehman, George M. Rodgers, Andre Crouch, Brian K. Whisenant, Wiliam H. Barry, Ramtin Agah, Joshua Holdstock, Shonda Hedge, Youssef Al-Saghir, Howard R. Lee, University of Utah Health Science Center, Salt Lake City, UT Background: The role of anticoagulation during percutaneous coronary intervention has been well established. However, the role of anticoagulation during diagnostic coronary angiography is less clear. Repeated exposure of the arterial circulation to the presence of catheters may result in thrombosis. PF1+2 and D-dimer have been reported to have signiﬁcant sensitivity and high negative predictive value in evaluating thrombotic phenomena. This pilot study was designed to detect whether signiﬁcant activation of coagulation occurs during diagnostic angiography via femoral approach by measurement of PF1+2 and D-dimer. Methods: Patients not on anticoagulation (except for aspirin) and without documented coagulopathy undergoing elective diagnostic coronary angiogram were enrolled in this prospective observational study. Blood samples of D-dimer and PF1+2 were obtained serially every 10 minutes to a maximum of 60 minutes or when the procedure is completed or anticoagulation was initiated for intervention. The data were analyzed in time interval correlation to the D-dimer level (STA LIATEST; Parsippany,NJ, ) and PF1+2 (ELISA;Germany). A D-dimer level ≥0.50 ug/ml was considered positive; a PF1+2 level ≥1.2 nmol/L was considered positive. Result: 20 patients were enrolled in this pilot study, 7 patients were female (35%) and 11 (55%) with diabetes. There were no systemic complications early or 2 weeks post procedure. Mean ﬂuoroscopic time was 7.8±7.81 minutes and average procedure time was 28±21.70 minutes. There was a signiﬁcant rise in PF1+2 (p<0.01) without signiﬁcant rise in D-dimer (p=0.94 and 0.98 for arterial and venous consecutively). Conclusion: There is an early rise of PF1+2, which suggests that the procedure triggered activation of coagulation. However, this phenomenon may not be clinically signiﬁcant, based on D-dimer measurements, for diagnostic coronary angiography lasting up to 30 minutes. Prophylactic anticoagulation is not necessary in stable patients without known thrombotic risk factors undergoing elective procedure. A larger study will be needed to investigate other patient populations. 1023-170 Plasma Levels of Fibrinogen, Plasminogen Activator Inhibitor -1, and Von Willebrand Factor Are Increased in Patients With Erectile Dysfunction Nikolaos Ioakeimidis, Charalambos Vlachopoulos, Konstantinos Rokkas, Ioanna Dima, Carmen Vassiliadou, Chrysoula Tselika, Marina Toutouza, Christodoulos Stefanadis, Athens Medical School, Hippokration Hospital, Athens, Greece Background: Erectile dysfunction (ED) may indicate increased cardiovascular risk. Fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (VWF) increase the tendency to thrombosis. The present study was undertaken to assess if altered thrombotic state determine ED in patients with or without coronary artery disease (CAD). Methods: A total of 121 men were studied: 39 men (aged 58±11 yrs) had ED without clinical evidence for CAD, 32 men (aged 61±8 yrs) had ED and CAD, 19 men (aged 59±11 yrs) had CAD and normal erectile function and 31 men (aged 57±6 yrs) were controls. Fibrinogen was measured by high sensitivity immunonephelometry. PAI and vWF were detected with ELISA. Results: There was a stepwise increase in ﬁbrinogen level from controls to CAD- no ED patients, to no CAD-ED patients, and then to ED plus CAD patients (p<0.001 ﬁgure). Moreover, circulating levels of PAI-1 and VWF were signiﬁcantly higher in men with ED plus CAD and in men with ED but no CAD as compared to controls and men with CAD and normal erectile function (p<0.01 and p<0.001, respectively). ACC_2006_8_VascularDisease.indd 365 1/4/06 5:21:32 PM 366A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n Conclusions: Circulating levels of ﬁbrinogen, PAI-1 and vWF are higher in men with ED of vascular origin with or without underlying CAD, indicating increased tendency to thrombosis. These ﬁndings may be related to the pathophysiology of the disease and may have implications for the increased cardiovascular risk in these patients. 1023-171 Anti-thrombotic Effect of Bivalirudin Compared With Eptiﬁbatide and Heparin in Diabetic Patients Undergoing Angioplasty: An Ex-vivo Human Study Eli I. Lev, Rajnikant Patel, Azim Karim, Amanda Kleiman, Juan J. Badimon, Neal S. Kleiman, The Methodist Hospital, Houston, TX, Mount Sinai Medical Center, New York, NY Background: Patients with diabetes who undergo percutaneous coronary intervention (PCI) are at high risk for thrombotic complications. We compared the anti-thrombotic effect of bivalirudin to eptiﬁbatide plus unfractionated heparin in diabetic patients undergoing elective PCI. Methods: Thirty diabetic patients were randomized to receive during PCI either bivalirudin (bival group, n=15) or eptiﬁbatide plus heparin (epti group, n=15) at standard dosing regimens. The drugs were continued for 20 min (bival group) or 18 hrs (epti group) following PCI. Blood thrombogenicity was assessed by the Badimon ex-vivo perfusion chamber. Each patient underwent two perfusion studies - at baseline (on aspirin and clopidogrel) and 15-20 min following PCI. Perfusion studies were performed at low and high shear rate (LSR, HSR) and porcine aortic tunica media served as thrombogenic surfaces. Total platelet-thrombus area and ﬁbrin deposition were measured by computerized planimetry. Results: There were no differences in baseline clinical characteristics or baseline thrombus or ﬁbrin area between the two groups. Comparisons between the groups in the reduction of thrombus and ﬁbrin area are shown below. Conclusions: Both bivalirudin and eptiﬁbatide plus heparin, given to diabetic patients during PCI, achieved marked reductions in total thrombus formation and ﬁbrin deposition. However, glycoprotein IIb/IIIa inhibition by eptiﬁbatide caused a more pronounced reduction in platelet-thrombus formation. Absolute and relative reduction in thrombus and ﬁbrin area among the two groups; mean±SD (%) Bival group (n=15) Epti group (n=15) P value HSR: mean reduction in thrombus area, µm2 (% decrease from baseline) 6823±2975 (69.5%) 9196±2886 (89.3%) 0.04 LSR: mean reduction in thrombus area, µm2 (% decrease from baseline) 3923±2972 (50.6%) 6407±3021 (73.2%) 0.03 HSR: mean reduction in ﬁbrin deposition, µm2 (% decrease from baseline) 1089±730 (46.9%) 1039±693 (48.6%) 0.8 1023-172 Added Ramipril to Simvastatin Shows Additive Effects on Tissue Factor Activity and Prothrombin Fragment 1+2 in Patients With Type 2 Diabetes Kwang K. Koh, Seung H. Han, Jeong Y. Ahn, Kyu J. Oh, Gachon Medical School, Incheon, South Korea Background: Tissue factor plays a pivotal role in thrombus formation. Experimental studies have demonstrated statins and angiotensin converting enzyme inhibitors attenuate the expression of tissue factor by different mechanism. Therefore, we investigated the effects of monotherapy and combined therapy on tissue factor activity. Methods: This was a randomized, double-blind, placebo-controlled cross-over trial with three treatment arms (each 2 months) and two washout periods (each 2 months). Fifty type 2 diabetic patients were given simvastatin 20 mg and placebo, simvastatin 20 mg and ramipril 10 mg, or ramipril 10 mg and placebo daily during each 2 month treatment period. Data= mean±SEM or median. Results: Simvastatin, ramipril, and combined therapy reduced plasma tissue factor activity from 0.531 to 0.462, from 0.544 to 0.504, from 0.638 to 0.428, respectively (P=0.056, P=0.167, and P<0.001, respectively). However, combined therapy changed to a greater extent than simvastatin or ramipril alone (P=0.029 by ANOVA). All three therapies signiﬁcantly reduced plasma prothrombin fragment 1+2 levels from 0.909 to 0.814, from 0.880 to 0.839, from 0.917 to 0.781, respectively (P=0.037, P=0.057, and P<0.001, respectively). Combined therapy changed to a greater extent than simvastatin or ramipril alone (P=0.040 by ANOVA). All three therapies changed plasma antithrombin III levels by -2±2%, 4±1%, and 7±2% from the respective baseline levels (P=0.078, P=0.014, and P=0.005, respectively). Combined therapy or ramipril alone signiﬁcantly increased antithrombin III levels to a greater extent than simvastatin alone (P=0.003 by ANOVA). All three therapies signiﬁcantly reduced plasma CD40 ligand levels from 3.26±0.35 to 2.61±2.46, from 3.17±0.48 to 1.87±0.34, and from 3.55±0.28 to 2.01±0.16 (P=0.098, P=0.002, and P<0.001, respectively). There were no signiﬁcant differences among three therapies (P=0.204 by ANOVA). Conclusions; Ramipril combined with simvastatin signiﬁcantly reduces plasma tissue factor activity and prothrombin fragment 1+2 levels to a greater extent than monotherapy with either drug in patients with type 2 diabetes. POSTER SESSION 1024 Coronary Artery Function, Lipids, and Atherosclerosis Progression Tuesday, March 14, 2006, 12:30 p.m.-4:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 12:30 p.m.-1:30 p.m. 1024-173 Testosterone, Estrogen, and Coronary Function in Women: A Report From the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study B. Delia Johnson, C. Noel Bairey Merz, Eloise E. Kaizar, Frank Z. Stanczyk, Vera Bittner, Sarah L. Berga, Glenn D. Braunstein, Barry L. Sharaf, Ricardo Azziz, T. Keta Hodgson, Carl J. Pepine, Sheryl F. Kelsey, Gregory O. von Mering, George Sopko, University of Pittsburgh, Pittsburgh, PA, Cedars-Sinai Medical Center, Los Angeles, CA Background: Current evidence suggests increased coronary artery disease risk in women with excess androgens. The role of endogenous testosterone and estrogens on coronary function in women has not been fully evaluated. Methods: We evaluated 60 postmenopausal women not taking exogenous hormones undergoing coronary angiography for suspected myocardial ischemia. Core laboratory analyses included bioavailable estradiol (E2) and bioavailable testosterone (T). Coronary function was assessed during angiography and included: 1. coronary ﬂow reserve (CFR) following administration of adenosine (ADO); 2. change in vessel diameter following acetylcholine (ACH). Measurements were performed by a blinded core laboratory. Results: Mean age was 61+9 years, 15% were non-white, 23% had obstructive CAD, 25% diabetes, and 57% had a history of smoking. Using age-adjusted partial correlations, the T/E2 ratio was positively associated with CFR (r=0.35, p=0.007) but not with diameter response to ACH (r=-0.12, p=0.52). These relationships remained consistent after adjusting for CAD presence and risk factors, including obesity. Conclusions: Among postmenopausal women evaluated for suspected ischemia, increased T/E2 ratio was associated with better coronary reactivity to ADO but not ACH. These results suggest that androgens may modulate vasomotor response related to smooth muscle (ADO) but not endothelial-dependent (ACH) function in these women. 1024-174 Impaired Atrial Coronary Flow Reserve in Patients With Lone Paroxysmal Atrial Fibrillation Emmanuel I. Skalidis, George E. Kochiadakis, Nikolaos E. Igoumenidis, Evangelos A. Zacharis, George Lirarakis, Dimitris Arfanakis, Panos E. Vardas, Heraklion University Hospital, Heraklion, Greece Purpose: The aetiology and the course of lone paroxysmal atrial ﬁbrillation (PAF) are poorly understood. Abnormal atrial histology, with myocardial ﬁbrosis and decreased microcapillary density has been found in atrial tissue samples from patients with PAF. The purpose of this study was to assess atrial microvascular function in these patients. Methods: Eight patients with lone PAF (at least 3 episodes over the last year) and normal ACC_2006_8_VascularDisease.indd 366 1/4/06 5:21:33 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 367A Vascular D isease, H ypertension, and P revention coronary arteries underwent coronary blood ﬂow velocity measurements, using a 0.014 inches Doppler guidewire in the left atrial circumﬂex branch (LACB). LACB was deﬁned as any branch that originated to the left of the left circumﬂex coronary artery and the coronary sinus, in the right anterior oblique view (at least 0.5 mm in diameter). Measurements were recorded at baseline (b) and at maximal hyperemia (h) after adenosine administration. CFR was calculated as the ratio of the time-averaged peak coronary ﬂow velocity (APV) at maximal hyperemia (h-APV) to the APV at baseline (b-APV). Eleven patients with normal coronary arteries, without history of PAF, served as a control group. Results: Table 1. Conclusions: Patients with lone PAF showed an impairment of atrial CFR. Although this has to be conﬁrmed in a larger patient population, it indicates that atrial microvascular dysfunction may be a causative and/or contributing factor for PAF in these pts. Table 1 Lone-PAF Controls b-APV cm/sec 19.6 + 8.2 16.1 + 5.3 p = NS h-APV cm/sec 42.4 + 15.3 47.0 + 16.6 p = NS CFR 2.3 + 0.6 2.9 + 0.7 p = 0.047 1024-175 Arachidonic Acid and Docosahexaenoic Acid Supplementation Increases Coronary Flow Velocity Reserve in Healthy Japanese Elderly Individuals Hiroki Oe, Takeshi Hozumi, Eriko Murata, Hitoe Matsuura, Kazuaki Negishi, Yoshiki Matsumura, Shinichi Iwata, Keitaro Ogawa, Kenichi Sugioka, Yasuhiko Takemoto, Kenei Shimada, Minoru Yoshiyama, Yoshiyuki Ishikura, Yoshinobu Kiso, Junichi Yoshikawa, Osaka City University Medical School, Osaka, Japan, Institute for Health Care Science, SUNTORY Ltd, Osaka, Japan Background: Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are important components of phospholipids and cell membranes. To determine the effects of ARA and DHA on coronary circulation, we assessed coronary ﬂow velocity reserve (CFVR) before and after ingestion of ARA and DHA. Methods: This was a double-blind, case-control, placebo-matched study of 28 healthy Japanese elderly people (19 men, 9 women, mean age 65 years) conducted to compare the effects of PUFA supplementation (ARA; 240mg/day, DHA; 240mg/day) and placebo (olive oil) on CFVR. Coronary ﬂow velocity (CFV) of the left anterior descending coronary artery (LAD) was measured at rest and at hyperemia during adenosine triphosphate (ATP) infusion (0.14mg/kg/min) by TTDE to determine CFVR. Results No new clinical events occurred during the intervention period. There was no signiﬁcant differences in CFV at rest and during hyperemia, or in CFVR at baseline in the 2 groups (PUFA supplements vs placebo; 17 ± 7 vs 16 ± 6, 62 ± 20 vs 59 ± 12, and 3.9 ± 1.0 vs 4.0 ± 0.8 cm/s, respectively). After 3-month supplementation, CFV during hyperemia was signiﬁcantly higher in the PUFA than in the placebo group (73 ± 19 vs 64 ± 12 cm/s, p<0.01) although no signiﬁcant difference was found between the two groups in CFV at rest (17 ± 7 vs 16 ± 4 cm/s). Thus, CFVR signiﬁcantly increased after PUFA consumption (3.9 ± 1.0 vs. 4.5 ± 1.0, p<0.01). After the 3-month intervention period, ARA and DHA in the erythrocyte membrane were signiﬁcantly increased in the group that had been taking PUFA supplements compared with the placebo group (ARA; 8.8 ± 1.5 vs 12.5 ± 1.4%, p<0.01, DHA; 6.0 ± 1.7 vs 10.4 ± 1.3%, p<0.01). There appeared to be good correlation between the magnitude of increase in RBC membrane ARA and increase in CFVR after 3 months of intervention (r = 0.57, y = 13.2x + 0.071, p=0.002). There was also a weaker but nonsigniﬁcant correlation between the increase in RBC membrane DHA and increase in CFVR (r = 0.24, y = 4.35x + 0.22, p=0.24) Conclusion: Three-month supplementation of ARA and DHA increases CFVR in healthy Japanese elderly individuals. The results of this study suggest that PUFA supplementation has beneﬁcial effects on coronary circulation. 1024-176 Atheromatous Coronary Plaque Has Lower Distensibility Than Fibrous Plaque: Comparison of Intravascular Ultrasound Imaging and Histo- Pathological Analysis Takashi Akima, Robert J. Siegel, Kiyoshi Iida, Huai Luo, Kohsuke Hagisawa, Kuniaki Nakanishi, Toshihiko Nishioka, Masatoshi Kusuhara, Fumitaka Ohsuzu, Toshiaki Kawai, Cedars-Sinai Medical Center, Los Angeles, CA, National Defense Medical College, Tokorozawa, Japan Background: The aim of this study is to assess the histo-pathological characteristics associated with coronary arterial distensibility. Methods: 79 coronary arteries were obtained from 59 autopsies (mean age 62 ± 13 years old, 39 male). All branches of the coronary arteries were ligated to create closed spaces. An intra-vascular ultrasound (IVUS) catheter was advanced into the coronary artery over a guide wire under ﬂuoroscopy. Intra-coronary arterial pressure was gradually increased every 20 mmHg up to 180 mmHg, all IVUS images were recorded on S-VHS tape and luminal area (LA) was serially measured later. Coronary arterial distensibility was calculated as following formulae; compliance = [maximum LA - minimum LA] / minimum LA / pressure gradients × 1000 (mmHg-1), stiffness index beta = [ln (maximum pressure/ minimum pressure)] / [(maximum diameter - minimum diameter)/minimum diameter]. At the end of the IVUS study, the imaged site was parafﬁn embedded for pathologic analysis. All specimens were histologically categorized into two groups, elastin-poor atheromatous plaque (n = 30) and elastin-rich ﬁbrous plaque (n = 49). Quantitative pathologic component analysis was performed using a digitized-computed system. Results: Arterial distensibility was signiﬁcantly lower in atheromatous plaque than ﬁbrous plaque; compliance was 1.4 ± 0.1 mmHg-1 in atheromatous plaque, 2.1 ± 0.2 mmHg-1 in ﬁbrous plaque (p=0.004), stiffness index � was 16.0 ± 2.4 in atheromatous plaque, and 9.9 ± 0.6 in ﬁbrous plaque (p=0.004). Multivariable analysis showed that pathological category, maximum wall thickness and % stenosis are independently related to both compliance (p=0.005, <0.001, 0.001, respectively) and stiffness index � (p=0.012, 0.037, 0.007, respectively). Conclusions: Our data indicate that the histo-pathologic characteristics of the arterial wall are important determinants of coronary arterial distensibility. 1024-177 Signiﬁcance of Lipid-content in Determining the Pattern of Coronary Arterial Remodeling: An Intravascular Ultrasound Study With Tissue Characterization by use of Wavelet Analysis Genta Hashimoto, Takafumi Hiro, Takashi Fujii, Takayuki Okamura, Jutaro Yamada, Yusaku Fukumoto, Masunori Matsuzaki, Yamaguchi University Graduate School of Medicine, Ube, Japan Background: It has been demonstrated that positive remodeling of coronary artery is related to vulnerability of plaque. However, tissue characteristics that determine the pattern of the remodeling are still unclear. Wavelet analysis of intravascular ultrasound images is a new mathematical model which can detect a special geometrical pattern inside the echo-signals of interest. We previously reported that wavelet analysis of IVUS images could identify a lipid core within plaques (J Am Coll Cardiol, 2005). Methods: To examine the relationship between remodeling pattern and lipid content of plaque, a total of 70 coronary plaque segments (averaged thickness: 1.68 ± 0.9 mm) were imaged with 40MHz IVUS. Remodeling index was calculated as vessel area of interest divided by reference vessel area. For the purpose of wavelet analysis, several linear echo- vectors were sampled from plaque images, and then processed with a time-frequency domain assessment of wavelet analysis using Daubechies-2 wavelet. This algorithm can provide a score of lipid content of the plaque of interest. Results: Expansive remodeling can be observed in 44 coronary segments (63%). The lipid content of this group was signiﬁcantly larger than that of the groups without expansive remodeling. The degree of remodeling index is signiﬁcantly correlated with lipid content score of coronary plaque ( p<0.0001, r=0.58). Conclusions: These data suggest that expansive remodeling is likely to occur at lipid-rich coronary segments. Therefore, coronary arterial remodeling might be associated not only with a compensatory mechanism for luminal stenosis, but also with plaque instabilization in terms of vulnerability. 1024-178 Follow-Up LDL-cholesterol Level as an Independent Predictor of Changes of Coronary Atherosclerotic Plaque Size: A Serial Intravascular Ultrasound Analysis Myeong-Ki Hong, Cheol Whan Lee, Young-Hak Kim, Bong-Ki Lee, Duk-Woo Park, Young-Hoon Jeong, Eui-Seock Hwang, Se-Whan Lee, Duk-Hyun Kang, Sang-Sig Cheong, Jae-Kwan Song, Jae-Joong Kim, Seong-Wook Park, Seung-Jung Park, Asan Medical Center, Seoul, South Korea Using serial intravascular ultrasound (IVUS), we identiﬁed the independent predictors of changes in coronary plaque size in relation to serum lipid levels. One-hundred three patients with non-stenotic coronary plaques underwent baseline and 12-month follow-up IVUS studies; 54 patients (52%) were treated with statins. Baseline IVUS study showed no statistical differences of mean external elastic membrane, lumen and plaque&media (P&M) area between statin-treated patients vs. non-statin-treated patients. Compared to non-statin-treated patients, changes in mean P&M area was signiﬁcantly larger in statin- treated patients (0.11±0.24mm2 vs. -0.20 ±0.30mm2, p<0.001). There was a positive relation between the changes in mean P&M area vs. follow-up LDL cholesterol, follow- up total cholesterol, changes of LDL cholesterol and changes of total cholesterol. In multivariate linear regression analysis, the only independent predictor of the changes in mean P&M area was follow-up LDL-cholesterol level (r=0.469, p<0.001, 95% CI=0.003- 0.006). The cut-off value of follow-up LDL-cholesterol for no change or a decrease in mean P&M area was less than 100mg/dl (Figure). Conclusions: The current 12-month follow-up IVUS study showed the follow-up LDL- cholesterol level was the only independent predictor of changes in coronary plaque size. When the patients achieved the follow-up LDL cholesterol level less than 100 mg/dl with statin treatment, no progression or regression of coronary plaque was expected. ACC_2006_8_VascularDisease.indd 367 1/4/06 5:21:33 PM 368A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n 1024-179 Low-dose Simvastatin Induces Positive Remodeling After Coronary Stenting in Normocholesterolemic Patients Young Joon Hong, Myung Ho Jeong, Ju Han Kim, Weon Kim, Young Keun Ahn, Jeong Gwan Cho, Jong Chun Park, Jung Chaee Kang, Chonnam National University Hospital, Gwangju, South Korea Background: Statins are effective lipid lowering and anti-inﬂammatory agents, and imaging studies have demonstrated their ability to slow progression and promote regression of atherosclerosis. However, few studies performed to date have used intravascular ultrasound (IVUS) to examine the effects of statin therapy on the inhibition of neointimal hyperplasia (NIH) in normocholesterolemic patients. Methods: This study included 80 normocholesterolemic patients who underwent intravascular ultrasound study (IVUS)-guided stenting for angiographically signiﬁcant stenosis. Patients were divided into two groups according to statin therapy (simvastatin group; n=42, 58.7±10.3 years, male 74%, non-simvastatin group; n=38, 57.8±10.8 years, male 78%). 20 mg simvastatin was given to statin group. 6-month follow-up quantitative coronary angiography and IVUS data were analyzed. Results: At 6-month after stenting, binary in-stent restenosis (ISR) was present in 19% of statin group and in 21.1% of non-statin group and repeat revascularization was performed in 16.7% in statin group and 18.4% in non-statin group (p=NS). NIH did not differ signiﬁcantly between the 2 groups (1.9 ± 0.8 vs 2.1 ± 0.9 mm2) and the remodeling index was signiﬁcantly higher in the statin group than that in the non-statin group (1.04±0.45 vs. 0.97±0.37, p=0.035) at 6-month follow-up. Major adverse cardiac events at 12 months were present in 21.4% of simvastatin group and 26.3% of non-simvastatin group. Conclusions: In normocholesterolemic patients undergoing coronary stenting, low-dose simvastatin therapy does not reduce ISR and does not inhibit intimal hyperplasia, but it induces positive remodeling of vascular segments containing atherosclerotic plaques after coronary stent implantation. POSTER SESSION 1025 Peripheral Arterial Markers of Disease Tuesday, March 14, 2006, 12:30 p.m.-4:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 12:30 p.m.-1:30 p.m. 1025-180 Use of Portable Ultrasound to Measure Carotid Intima- Media Thickness Sascha Goonewardena, Georgeanne Lammertin, R. Parker Ward, Roberto M. Lang, Jeanne M. DeCara, University of Chicago, Chicago, IL Carotid intima-media thickness (CIMT) is useful in predicting cardiovascular events even in patients without clinically evident atherosclerosis. The utility of this index would be greatly enhanced if it could be obtained in an ofﬁce-based practice. Methods: B-mode ultrasound of the right and left carotid artery was performed in 52 unselected patients by a single sonographer using a full platform (ie33, Philips) and a portable system (Titan, Sonosite). Mean CIMT measurements of the far wall of the common carotid artery within 1 cm of the bulb were obtained using automated edge detection software (Q-Lab, Philips; Sonocalc, Sonosite). Inter-technique agreement was assessed using Bland-Altman analysis. Intra- and inter-observer variability was determined in a subset of 10 patients by performing repeated measurements. Results: Inter-technique agreement for measurements made with the full platform and the portable system was high with a 7% bias. Inter-observer variability for the full platform system was 4%, and 6% for the portable system. However, intra-observer variability was more than twice higher for the portable system than the full platform (8.5% vs 3.5%). Conclusion: Portable ultrasound compares well with standard full platform for CIMT measurements. Although this new portable technology lends itself well to bedside assessment of CIMT and cardiovascular risk assessment at the time of patient encounter, it may not be ideal for serial CIMT measurements given its lower reproducibility. 1025-181 Increased Aortic Characteristic Impedance Contributes to Increased Central Aortic Pulse Pressure in Young Women With Type 1 Diabetes Nancy K. Sweitzer, James H. Stein, Mitul Vyas, Michele L. Zimbric, Gary F. Mitchell, University of Wisconsin, Madison, WI, Cardiovascular Engineering, Inc., Holliston, MA Background: Increased pulse pressure (PP) in patients with type 2 diabetes mellitus (DM) is related to increased arterial stiffness. Often elevated mean arterial pressure (MAP) complicates interpretation because arterial stiffness increases with elevated MAP. Methods: We evaluated pulsatile hemodynamics in 13 young women with type 1 DM and 13 age-matched controls from the Cardiovascular Disease in Type 1 Diabetes (Cardio-Diab) Study. Arterial tonometry and left ventricular outﬂow tract Doppler ﬂow and diameter were used to compute aortic characteristic impedance (Zc= early change in carotid pressure / ﬂow). Carotid-femoral pulse wave velocity (PWV) was calculated from body surface measurements and tonometry foot-foot time delay. Augmentation index (AI) was assessed from the carotid waveform. Results: Mean ages were 28 ± 7 (DM) and 29 ± 9 (control). Brachial systolic, diastolic and mean pressures did not differ; however, brachial and carotid PP were elevated in DM (Table). Zc was markedly elevated in DM, while PWV and AI did not differ. Conclusions: Young women with type 1 DM had elevated PP, which was linked to elevated Zc and increased forward pressure wave amplitude. MAP, PWV and AI were normal. Since increased pressure pulsatility is known to promote atherogenesis in large arteries and adverse remodeling and rarefaction in the microcirculation, abnormal matching between aortic ﬂow and Zc may represent an early mechanistic link in the pathogenesis of macro- and microvascular complications of DM. Arterial Stiffness Parameters in Type 1 Diabetes Mellitus (mean +/- SD) DM No DM p value Brachial systolic pressure, mmHg 112 +/- 14 106 +/- 11 ns Brachial diastolic pressure, mmHg 58 +/- 10 64 +/- 11 ns MAP, mmHg 79 +/- 10 80 +/- 12 ns Brachial PP, mmHg 54 +/- 13 42 +/- 9 0.004 Carotid PP, mmHg 47+/- 13 36+/- 9 0.02 Zc, dyne*sec/cm 5 184+/- 68 135 +/- 41 0.009 Peak aortic ﬂow, ml/s 331 +/- 53 333 +/- 68 ns PWV, m/s 5.9 +/- 0.9 5.9 +/- 0.8 ns AI, % 2.1 +/- 12.6 -1.3 +/- 16.1 ns 1025-182 Carotid Stenting Induces Platelet Activation and a Pro- inﬂammatory Response Elie Y. Chakhtoura, Jonathan E. Goldstein, Robert W. Hobson, II, Saint Michael’s Medical Center, Newark, NJ, UMDNJ, Newark, NJ Background: Platelet activation and inﬂammation play a key role in ischemic thrombotic complications after coronary interventions. The purpose of this study is to determine the effect of carotid stenting on platelet activation and inﬂammatory signaling. Methods & Results: We prospectively enrolled 37 patients (age = 71 ± 9 years, 19 women and 18 men) who underwent carotid stenting (CS) between April 2003 and July 2005. Systemic venous blood samples were collected at baseline (h0) prior to CS, 1 hour (h1), 4 hours (h4), and 24 hours (h24) after. Using ﬂow cytometry, the expression of the activation-dependent epitope CD62P on the platelet surface was analyzed on all samples (h0 through h24). High-sensitivity C-reactive protein (HS-CRP) was analyzed by nephelometry on the samples collected at h0 and h24. CD62P expression increased 2.5-fold (from 3.63 ± 1.59 to 9.34 ± 3.57 %, p<0.001) within 1 hour of CS and increased further to 3.9-fold (to 14.45 ± 5.31 %, p<0.001) at 4 hours, and 6.5-fold (to 21.79 ± 7.62 %, p<0.001) at 24 hours. HS-CRP increased 4-fold from 2.01 ± 0.84 to 8.17 ± 3.59 mg/L, p<0.001. The mean clinical follow-up was 15 ± 8 months. All patients remained free of stroke or restenosis. Conclusion: The present study demonstrates that CS causes platelet activation and a pro-inﬂammatory response as evidenced by the elevation in the study markers CD62P and HS-CRP. These ﬁndings may lead to a more aggressive pre-procedural antiplatelet therapy as well as a possible role for high-dose HMG-CoA reductase- inhibitor therapy. 1025-183 The Relationship Between Regional Left Ventricular Wall Motion and Troponin-I Levels in Patients With Subarachnoid Hemorrhage: Results of the SAHMII study Masaki Tanabe, Michael B. Horowitz, Maxime Cannesson, Marilyn Hravnak, Elizabeth A. Crago, John Gorcsan, III, University of Pittsburgh, Pittsburgh, PA Background: Although cardiac effects after aneurysmal subarachnoid hemorrhage (SAH) are observed, their details remain poorly understood. Accordingly, we studied the relationship of elevations of cardiac troponin-I and left ventricular (LV) wall motion abnormalities in patients (pts) with SAH as part of the SubArachnoid Hemmorhage Myocardial Infarction and Ischemia (SAMII) study. Methods: Fifty consecutive pts (aged 54±9 yrs, 78% women) with aneurysmal SAH documented by angiography and CT (Fisher mean severity score 2.86) were prospectively studied with troponin-I and echo < 48 hrs after SAH and at 5-7 days. A LV wall motion score (WMS) was derived using a standard 16-segment model. Maximum of daily troponin-I was used as a marker of myocardial injury. Results: Ten pts (20%) had elevated cardiac troponin-I (>1.1ng/ml) and 11 (22%) showed abnormal WMS (1.3±0.2) acutely. Three pts then recovered to normal WMS at the follow- up. No pts with normal WMS during the acute echo study showed abnormal wall motion at follow-up. Troponin-I levels of pts with abnormal WMS were signiﬁcantly higher than those ACC_2006_8_VascularDisease.indd 368 1/4/06 5:21:34 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 369A Vascular D isease, H ypertension, and P revention with normal WMS: 6.5±12.8ng/ml vs. 0.3±0.5, respectively, (p<0.05). Troponin-I levels >1.1ng/ml predicted WMS abnormalities with 55% sensitivity and 92% speciﬁcity. Conclusions: Evidence of cardiac injury by elevated troponin-I level and/or regional wall motion abnormalities occur in an important subset of pts with SAH. Elevated troponin-I is highly speciﬁc for predicting regional LV dysfunction with SAH. 1025-184 Do Duplex Ultrasound Velocities Accurately Reﬂect Angiographic Stenosis in Recently Stented Carotid Arteries? Anjli Maroo, David S. Lee, Alex Abou-Chebl, Samir R. Kapadia, Deepak L. Bhatt, Christopher T. Bajzer, Jay S. Yadav, Cleveland Clinic Foundation, Cleveland, OH Background: Although duplex ultrasound (US) is the most widely utilized tool for surveillance of stented carotid arteries, velocity characteristics of stented arteries are not well described. We aimed to determine whether duplex velocities of recently stented carotid arteries correlate with angiographic stenosis or with B-mode determination of stent patency. Methods: We examined 131 patients who underwent internal carotid artery stenting and surveillance carotid US soon after stenting. Modiﬁed Strandness criteria for native carotid arteries were used to estimate % diameter reduction by US. Angiographic % ﬁnal stenosis was visually estimated by NASCET criteria. B-mode imaging was used to qualitatively assess stent patency. Results: The mean age was 72 ± 9 years, mean stent diameter was 7.5 ± 0.9 mm, and mean stent length was 28 ± 9mm. Peak systolic velocity (PSV) ≥ 105 cm/sec (corresponding to > 40% stenosis by established US criteria) was observed in 57/131 patients (42%). There was no difference in ﬁnal % angiographic stenosis between those with elevated versus normal duplex velocities (Table). B-mode imaging indicated that the stents were widely patent in 51/57 patients. Conclusions: In recently stented carotid arteries, duplex ultrasound velocities do not accurately reﬂect residual angiographic stenosis. Hence, the absolute values of duplex ultrasound velocities in stented carotid arteries should not be overinterpreted. PSV ≥105 PSV< 105 P Value n 57 74 % angiographic stenosis 7±11 5±8 0.12 PSV (cm/sec) 135±28 83±15 <0.001 EDV (cm/sec) 37±22 24±8 <0.001 ICA:CCA ratio 2.0±0.8 1.0±0.3 <0.001 (PSV=peak systolic velocity; EDV=end-diastolic velocity; ICA:CCA ratio=internal carotid artery:common carotid artery ratio of PSV; values are expressed as mean ± standard deviation) POSTER SESSION 1026 Lipids, BP, Sildenaﬁl and Stiffness Tuesday, March 14, 2006, 12:30 p.m.-4:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 12:30 p.m.-1:30 p.m. 1026-185 The Addition of Niacin to Statin Therapy Produces an Atheroprotective Shift in Lipoprotein Subclasses and Inﬂammatory Markers in Patients With Coronary Artery Disease and Well-Controlled LDL-Cholesterol Devang M. Dave, Kathleen A. Sliney, Paula Mooney, Carey D. Kimmelstiel, Ayan R. Patel, Richard H. Karas, Jeffrey T. Kuvin, Tufts-New England Medical Center, Boston, MA Background: Lipid management guidelines focus on aggressive lowering of low-density lipoproteins (LDL) and the need for broader use of therapies aimed at increasing high- density lipoprotein (HDL) levels. However, little is known about the effects of adding HDL-raising therapies in individuals who have achieved target LDL levels. We examined the effects of niacin on lipoprotein particle size distribution and inﬂammatory markers in subjects with coronary artery disease (CAD) and well-controlled LDL levels. Methods: Fifty-four patients with stable CAD and LDL <100 mg/dL were randomized to receive Niaspan ER® 1000mg (Kos Pharmaceuticals) or placebo for 12 weeks in a blinded fashion. Blood samples obtained at baseline and study conclusion were analyzed for subparticle concentrations using NMR spectroscopy as well as lipoprotein-associated phospholipase A2 (Lp-PLA2) and C-reactive protein (CRP). Results: The average age was 58±9 years (mean±SD; range 42-77), 93% were male and 96% were on stable statin therapy. Baseline fasting total cholesterol, HDL, LDL, and triglyceride levels were 139±20, 40±7, 77±16, and 124±45 mg/dL, respectively. After 3 months, niacin therapy increased HDL by 8% (p<0.01) and decreased triglyceride levels by 15% (p<0.01), without signiﬁcantly altering total cholesterol or LDL levels. Niacin increased large particle HDL by 32% (p<0.001) and decreased small particle HDL by 8% (p<0.005). Similarly, niacin increased large particle LDL by 82% (p=0.09) and decreased small particle LDL by 12% (p<0.01). Niacin also decreased Lp-PLA2 (284±83 to 217±55 ng/mL; p<0.001) and CRP levels (6.5±9 to 3.0±3 mg/L; p=0.03). Lipoprotein and inﬂammatory parameters did not change in patients receiving placebo. Conclusions: Over a three month period, niacin favorably shifts the ratio of small:large HDL particles, the distribution of LDL subparticles, and inﬂammatory markers in CAD patients already on statin therapy. These data suggest that the addition of niacin is beneﬁcial in high risk patients with treated LDL levels. The extent to which these salutary changes contribute to a reduction in clinical events requires further study. 1026-186 After Adjustment for Confounding Variables, Treatment With Statin Therapy at Baseline but Not Low LDL- cholesterol Levels Results in Better Two-Year Outcome in Patients With Established Angiographic Coronary Disease Sanjaya Khanal, Mouaz Al-Mallah, Ajay Srivastava, Mohamad Sinno, Henry Ford Heart and Vascular Institute, Detroit, MI Background: In patients with established coronary artery disease (CAD), statin therapy reduces cardiovascular events. It is not clear however, whether this is due to treatment of statin therapy or low cholesterol levels. We hypothesized that in patients with established CAD, statin therapy not low serum LDL-cholesterol levels (LDL) improves outcome. Methods: We divided 1192 patients prospectively enrolled in the Active Lipid Management in Coronary Artery Disease Study into two groups with baseline LDL < or > 100 mg/dl. Baseline demographics, clinical characteristics and 2-year major cardiovascular events (MACE) were compared between the two groups. Multivariate analysis was done using signiﬁcant baseline covariates. Results: Signiﬁcant baseline variables between the two groups are listed in the table. Unadjusted MACE was higher in the group with LDL <100 mg/dl (20% vs 15%, p=0.03). After adjustement for signiﬁcant baseline variables, statin therapy at enrollment (OR 0.67, 95% CI 0.45-1.0, p=0.05) but not LDL <100mg/dl (OR 1.35, 95% CI 0.91-2.0, p=0.14) was associated with 2-year MACE. Conclusions: There were signiﬁcant baseline differences in patients with angiographic CAD and have LDL< or >100mg/dl. After adjustment for baseline differences, statin therapy but not LDL <100mg/dl was associated with better clinical outcome at two years. Comparison of Patients with baseline LDL more than or less than 100mg/dl Variable LDL <100mg/dlN=640 LDL >100mg/dl N=552 p-value Age (mean +SD) 65.9+10.3 62.6+11.5 0.002 Female (%) 35 41 0.02 Diabetes (%) 41 28 <0.001 LDL mg/dl (mean +SD) 76.1+15.7 133.0+29.1 <0.001 HDL mg/dl (mean +SD) 42.2+12.3 44.6+12.7 0.001 Triglycerides mg/dl (mean +SD) 130.9+68.7 145.7+69.5 <0.001 Baseline statin use (%) 74 54 <0.001 LDL (2-year) mg/dl (mean+SD) 82.4+27.5 100.5+35.5 <0.001 1026-187 Relation of Left Atrial Enlargement to Various Haemodynamic, and Humoral Parameters in Patients With Essential Hypertension Efstathios Taxiarchou, Costas Tsiouﬁs, Pavlos Stougiannos, Dimitris Chatzis, Apostolis Kakkavas, Vagelis Chatzistamatiou, Christodoulos Stefanadis, Ioannis Kallikazaros, Hippokration Hospital, Athens, Greece Background: Left atrial (LA) enlargement, an early sign of hypertensive disease, is associated with increased cardiovascular risk. We investigated the correlation of various haemodynamic, and humoral parameters with LA enlargement in essential hypertensives. Methods: We studied 94 consecutive, newly diagnosed subjects (aged 51 years), with stage I- II essential hypertension [ofﬁce blood pressure (BP) =156/101 mmHg], without left ventricular hypertrophy and 34 normotensives, matched for age and sex. Based on 24-hour ambulatory BP monitoring, they were classiﬁed to dippers (n=60) and non-dippers (n=34), and also their plasma Brain Natriuretic Peptide (BNP) levels were determined. LA volume was evaluated, and was indexed for body surface area to estimate LA volume index (LAVI). Results: Hypertensives compared to normotensives had greater but not statistically signiﬁcant BNP levels (20.4vs17.1 pg/ml, p=NS), signiﬁcantly increased ofﬁce systolic, and diastolic BP (156vs130, and 101vs83 mmHg, respectively, p<0.0001 for both) as well as 24-hour systolic, and diastolic BP (143 vs 117, and 89 vs 71 mmHg, p<0.0001 for all), left ventricular mass index (LVMI) (105vs84gr/m2, p<0.0001), LA diameter (39±4 vs 36±4mm, p<0.0001), LA volume (44±13 vs 36±9ml, p=0.005), and LAVI (22±6 vs ACC_2006_8_VascularDisease.indd 369 1/4/06 5:21:34 PM 370A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n 19±5 ml/m2, p<0.05). LA volume, and LAVI did not differ in non-dippers compared to dippers. In the entire study population, LAVI exhibited positive relationships with LVMI (r=0.405, p<0.0001), ambulatory pulse pressure (r=0.269, p=0.012), and BNP (r=0.458, p<0.0001), while no correlation was found between LAVI, and daytime-nighttime systolic, and diastolic BP fall. In multiple linear regression analysis only LVMI, and BNP levels were signiﬁcantly associated with LAVI (beta= 0.279, p=0.04 and beta=0.340, p=0.006, respectively). Conclusions: In newly diagnosed essential hypertensive subjects, LA enlargement is associated with increased ambulatory pulse pressure, LVMI, and plasma levels of BNP. However, for the same ambulatory systolic, and diastolic BP, LA size seems not to be affected by the dipping status. The clinical signiﬁcance of these ﬁndings remains to be elucidated in future studies. 1026-188 Long- Term Sildenaﬁl Administration Improves Aortic Stiffness and Wave Reﬂections in Patients With Erectile Dysfunction of Vascular Origin Charalambos Vlachopoulos, Nikolaos Ioakeimidis, Konstantinos Rokkas, Konstantinos Aznaouridis, Nikolaos Alexopoulos, Konstantinos Tzannos, Athanasios Askitis, Christodoulos Stefanadis, Athens Medical School, Hippokration Hospital, Athens, Greece Background: Aortic stiffness and wave reﬂections are prognosticators of cardiovascular risk. We have previously shown that sildenaﬁl has an acute beneﬁcial effect on aortic stiffness. Whether sildenaﬁl has a long-term beneﬁcial effect on aortic stiffness and wave reﬂections with chronic daily administration has not been determined. Methods: The effects of a 2-week long treatment with sildenaﬁl on aortic stiffness were studied in 11 men (age 58±15 yrs) with vasculogenic erectile dysfunction (ED). The study was carried out on two separate arms, one with sildenaﬁl (100 mg) daily and one with placebo according to a randomized, placebo-controlled, double-blind, cross over design. All measurements were performed 24 hours after the last sildenaﬁl intake. Carotid- femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness using an automated, non-invasive device (Complior®) and augmentation index (AIx) as a measure of wave reﬂections using a validated system (Sphygmocor®). Results: Daily sildenaﬁl intake led to a signiﬁcant sustained decrease in PWV and AIx, indicating a decrease in aortic stiffness and wave reﬂections (p<0.05, ﬁgures). There were no signiﬁcant changes in systolic and diastolic pressure. Conclusions: This study shows for the ﬁrst time that chronic treatment with sildenaﬁl has a favourable effect on aortic stiffness and wave reﬂections in patients with ED. This ﬁnding may have important implications for patients receiving sildenaﬁl therapy for ED. 1026-189 Lack of Relationship Between Body Mass Index and Atherogenic Dyslipidemia in Asian Indians Suresh Mulukutla, Oscar Marroquin, Kevin Kip, Aryan Aiyer, Swaytha Ganesh, Saradha Subramanian, Rekhi Varghese, Steven Reis, University of Pittsburgh, Pittsburgh, PA Background: Body-mass index (BMI) is increasingly being utilized as a surrogate measure of underlying metabolic abnormalities that may predispose patients to cardiovascular disease. However, certain ethnic populations such as South Asians, exhibit adverse cardiovascular and metabolic risk proﬁles in spite of having more favorable anthropometric measures. The precise relationship between lipid parameters and BMI has not been fully evaluated in this population. Methods: We compared the fasting vertical auto proﬁle lipid results and BMI of 241 indigenous Asian Indians with those of 698 white Americans and 519 African-Americans. Results: Asian Indians had signiﬁcantly lower BMI, total cholesterol, LDL, and non HDL cholesterol compared with whites or blacks. However, they had signiﬁcantly lower HDL and higher triglyceride levels, in spite of not having the typical associated anthropometric properties. Using ATP III criteria, the prevalence of abnormal HDL and triglycerides was highest in Asian Indians; importantly, these measures were unrelated to BMI. This is in contrast to whites where BMI strongly predicts HDL and triglycerides, and African Americans where BMI strongly predicts HDL (Figure). Conclusions: Atherogenic dsylipidemia is prevalent among Asian Indians, and its presence in any given individual of South Asian descent cannot be predicted from BMI. In this population, more aggressive monitoring and therapy of dyslipidemia may be required without reliance on BMI as a surrogate marker. 1026-190 Effect of Metoprolol CR/XL on Diurnal Variation in Pulmonary Artery Pressure Measured Noninvasively Using First in Human Implant Responding to Ultrasonic Signals Keyur H. Parikh, Hetal D. Shah, Milan C. Chag, Urmil G. Shah, Hemang A. Baxi, Anish H. Chandarana, Ajay M. Naik, Joyal N. Shah, Yoseph Rozenman, Finn Waagstein, Ake Hjalmarson, The Heart Care Clinic, Ahmedabad, India, Goteberg University, Goteberg, Sweden Background: Beta Blockers have been shown to improve morbidity and mortality in Congestive Heart Failue (CHF). However, diurnal variation in Pulmonary Artery Pressure (PAP) may have important consequences in CHF. Remon CHF implant (Remon Technologies,Israel) is an innovative device for the noninvasive monitoring of PAP (systolic and diastolic).This study investigates the effect of Metoprolol CR/XL (MXL) on diurnal variation in PAP in CHF patients. Methods: It was a First In Man, prospective single arm study.10 NYHA class III/IV CHF patients with LVEF 26.5 ± 4.3 % were enrolled for the Remon CHF Implant placed via internal jugular vein permanently in the Right PA. Using ultrasonic signals it generates the PAP waveforms on a desktop system. After the implantation, ambulatory patients were noninvasively monitored for PAP every 2 hourly in day time and every 3 hourly during night for few days. All patients recieved conventional therapies except betablockers.After a month, MXL 25 mg/day was loaded in the patients and uptitrated two weekly by the MERIT-HF criteria. Diurnal measurement was repeated after the patients reached 100mg/d dose. Results: For the whole group, the baseline mean(±SD) daytime PAP was 29.19(±1.13)mm Hg systolic and 14.29(±0.54)mm Hg diastolic. During the night, systolic PAP rose to 31.84(±0.54)mm Hg (p<0.001) and the diastolic to 16.18(±0.50)mm Hg (p<0.001). After 100mg metoprolol CR/XL therapy, the mean(±SD) daytime PAP rose to 32.9(±9.3)mm Hg systolic(p=0.04) and 14.93(±6.1)mm Hg diastolic(p= NS). The mean(±SD) night PAP was 35.85(±10.6)mm Hg systolic and 17.22(±6.5)mm Hg diastolic. There was an overall rise of +4.49(±3.68) mm Hg and +1.37(±2.44) mm Hg in daytime systolic and diastolic PAP respectively. A nocturnal rise of +4.55(±3.5) mmHg and +1.76(±2.5) mmHg in systolic and diastolic PAP respectively was observed in MXL loaded patients. These patients will be monitored regularly for diurnal changes upto 6 months. Conclusions: Patients with CHF do show nocturnal rise in their PAP, which after Metoprolol CR/XL therapy shows further asymptomatic noctural rise in PAP . This supports the recommendation for slow and careful up-titration of MXL in such patients. POSTER SESSION 1027 Medication Effects Tuesday, March 14, 2006, 12:30 p.m.-4:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 12:30 p.m.-1:30 p.m. 1027-191 Aliskiren, an Oral Renin Inhibitor, Provides Dose- Dependent Efﬁcacy, and Placebo-Like Tolerability in Patients With Hypertension Byung-Hee Oh, Jenny Chung, Mahmudul Khan, Deborah Keefe, Andrew Satlin, Seoul National University College of Medicine, Seoul, South Korea, Novartis Pharmaceuticals, East Hanover, NJ Background: Aliskiren is the ﬁrst in a new class of orally effective renin inhibitors for the treatment of hypertension. This study evaluated the antihypertensive efﬁcacy, safety and tolerability of aliskiren in patients with mild-to-moderate hypertension (mean sitting diastolic blood pressure [DBP] 95 to <110 mmHg). Methods: Randomized, double-blind, multicenter, placebo-controlled study. Single-blind placebo run-in for 2-4 weeks, then randomization (672 patients) to aliskiren 150, 300 or 600 mg, or placebo once-daily for 8 weeks. Results: All aliskiren doses signiﬁcantly lowered DBP and mean sitting systolic blood pressure (SBP) compared with placebo (p<0.0001). Aliskiren 150, 300 and 600 mg ACC_2006_8_VascularDisease.indd 370 1/4/06 5:21:35 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 371A Vascular D isease, H ypertension, and P revention reduced DBP (least squares mean±SEM) by 10.3±0.63, 11.1±0.64 and 12.5±0.64 mmHg, respectively, vs 4.9±0.64 mmHg for placebo. Aliskiren 150, 300 and 600 mg reduced SBP by 13.0±1.0, 14.7±1.0 and 15.8±1.0 mmHg, respectively, vs 3.8±1.0 mmHg for placebo. The proportion of treatment responders (≥10 mmHg reduction in DBP and/or DBP <90 mmHg at endpoint) was signiﬁcantly higher (p<0.0001) in patients receiving aliskiren 150 mg (59%), 300 mg (63%), or 600 mg (69%) vs placebo (36%). All 3 aliskiren doses were statistically superior to placebo in reducing mean ambulatory DBP over the 24 h dosing interval (p<0.0001), with no apparent loss of effect at trough. Aliskiren was well tolerated with an adverse event (AE) rate similar to placebo at doses up to 300 mg. AE rates for aliskiren 150, 300 or 600 mg were 40.1, 46.7 or 52.4%, respectively, compared with 43.0% for placebo. The higher rate in the 600 mg group is probably accounted for by a greater incidence of diarrhea at this dose (11.4% vs 1.2, 1.8 and 1.2% for aliskiren 150, 300 mg and placebo, respectively). The incidence of serious AEs was similar for all groups (0.0-1.2%). Conclusions: Aliskiren 150-600 mg effectively lowers blood pressure in a dose- dependent manner in patients with mild-to-moderate hypertension. These effects were sustained over the 24 h dosing interval. Clinically relevant responder rates were seen at all doses. Aliskiren had placebo-like tolerability at doses up to 300 mg. 1027-192 Effects of Nitric Oxide Donor, Molsidomine, on Blood Pressure in Patients With Isolated Systolic Hypertension Seong-Hoon Lim, Jeong Hoon Yang, Soo Jin Cho, Ji Dong Sung, Seung Woo Park, Eun Seok Jeon, Sang Hoon Lee, Kyung Pyo Hong, Jeong Euy Park, Samsung Medical Center, Seoul, South Korea Background: Isolated systolic hypertension(ISH) may have a relation to the endothelial dysfunction, characterized by decreased bioavailability of nitric oxide (NO). Exogenous nitrate has been shown to reverse these changes, resulting in increased arterial compliance, vasodilation and decreased systolic blood pressure. Molsidomine is a direct nitric oxide donor which dilates venous capacitance. The purpose of the present study was to assess of the efﬁcacy of molsidomine, a nitric oxide donor, in lowering SBP to a target of < 140 mmHg in the patients with ISH refractory to conventional treatments. Methods: A total of 35 elderly patients were enrolled the subjects for this study. We deﬁned uncontrolled ISH as systolic blood pressure(SBP) >140 mmHg and diastolic blood pressure (DBP) < 90 mmHg despite conventional antihypertensive treatments. All the subjects have undergone treatment with various regimens of conventional antihypertensive agents given in combination. Additionally, they received nitric oxide donor, molsidomine, 2 mg twice a day for continuous period of 6 months. Ofﬁcial blood pressure was measured at three and six months after molsidomine treatment. Results: Their mean age (+ SD) was 73.4 ± 6.6 year (M:F=18:17). The mean values (+ SEM) for systolic and diastolic blood pressure at baseline were 157 + 2 mmHg and 73 + 1 mmHg, respectively. After 3 and 6 months of treatment, molsidomine resulted in signiﬁcant reduction in SBP with a daily dose of 4mg (mean change in SBP from baseline; -17.5 mmHg and -16.9 mmHg, respectively). There were no signiﬁcant changes in DBP (-1.4 mmHg and -3.1 mmHg, respectively) and heart rate. There were not any signiﬁcant side effects from molsidomine treatment. Conclusions: The present study demonstrates that long-term treatment with nitric oxide donor molsidomine in patients with uncontrolled ISH results in signiﬁcant reduction in systolic blood pressure. The long-term antihypertensive efﬁcacy of this agent appears to justify a trial of its use as an adjunct to conventional combined treatment in patients with uncontrolled ISH. 1027-193 Does the Presence of Hypertension Affect Cardiovascular Beneﬁts of Statin Therapy? Results From a Meta-regression Analysis of 69,984 Patients Franz H. Messerli, Lionel Pinto, Simon Tang, Kamlesh M. Thakker, Joseph C. Cappelleri, Tina Sichrovsky, Robert Dubois, St. Luke’s-Roosevelt Hospital, New York, NY, Cerner Health Insights, Beverly Hills, CA Background: The ASCOT-LLA and ALLHAT-LLT trials provide conﬂicting evidence of the effectiveness of statins in reducing CV morbidity and mortality in hypertensive patients. Objective: To put these ﬁndings in perspective, we performed a meta-analysis to determine the overall effectiveness of statins among hypertensive and non-hypertensive patients enrolled in other trials. Methods: We systematically reviewed MEDLINE publications from 1985 onwards for placebo-controlled randomized trials that examined the effect of statins on cardiac morbidity and mortality. Only trials that followed at least 1000 patients for two or more years were included in the meta-analysis. Outcomes of interest included cardiac or cardiovascular death, major coronary events, or major cardiovascular events. Pooled estimates of relative risk were calculated separately for (i) trials that prospectively randomized hypertensive patients to statin therapy (ASCOT-LLA & ALLHAT-LLT); (ii) trials that provided post-hoc cardiac event rates for subgroups of hypertensives and non-hypertensives; (iii) trials that provided only the baseline percentage of hypertension in the trial population; and, (iv) trials in (ii) and (iii) combined. The moderating effect of the percentage of hypertensives at baseline on the effectiveness of statins was tested using meta-regression. Results: Besides the ASCOT-LLA and ALLHAT-LLT, 12 trials enrolling a total of 69,984 patients met the inclusion criteria. Overall, in these 12 trials, statin therapy reduced cardiac death by 24% (RR = 0.76; 95% CI: 0.71 - 0.82). Pooled relative risk for cardiac morbidity and mortality was similar for trials in groups i, ii, iii, and iv and ranged from 0.73 - 0.78. Relative risk estimates for hypertensive (RR = 0.78; 95% CI: 0.72 - 0.84) and non- hypertensive (RR = 0.76; 95% CI: 0.72 - 0.80) subgroups were also similar. Consistent with the subgroup analysis, the meta-regression showed that the effect of statins on cardiac morbidity and mortality was not moderated by the percentage of hypertensives at baseline (Q estimate = 1.48; P = 0.22). Conclusion: Statin therapy effectively reduces CV morbidity and mortality in both hypertensive and non-hypertensive patients. 1027-194 Tetrahydrobiopterin: A Novel Anti-hypertensive Therapy Markus Porkert, Salman Sher, Uma Reddy, Faiz Cheema, Christina Niessner, Paul Kolm, Dean Jones, Craig Hooper, W. Robert Taylor, David Harrison, Arshed A. Quyyumi, Emory University, Atlanta, GA Background: Tetrahydrobiopterin (BH4) is a cofactor for nitric oxide(NO) synthesis. Reduced BH4 bioavailability, partly due to BH4 oxidation, uncouples NO synthase, decreases NO production and increases superoxide production and may contribute to hypertension. BH4 administration can lower blood pressure (BP) in experimental models. We hypothesized that oral BH4 will reduce BP and improve endothelial function in hypertension. Methods: In Study 1, the onset and duration of action of oral BH4, and in Study 2 its’ dose-response was studied in hypertensive subjects. In Study 1, 8 subjects with poorly controlled hypertension (BP>135/85 mmHg) despite medical therapy received either BH4 10mg/kg/day (n=4) or 5mg/kg/day (n=4) in two divided doses orally for 8 weeks. In Study 2, 8 subjects received 200 mg b.i.d and 8 received 100 mg b.i.d of BH4 for 4 weeks after an initial 2-week run-in period. Weekly measurements of BP were made during and 4 weeks after discontinuation of therapy, and endothelial function was measured as ﬂow- mediated vasodilation (FMD) of the brachial artery. Results: Study 1: Signiﬁcant reduction in systolic (p=0.005) and mean BP (p=0.01) was observed with BH4 at both doses. Systolic BP was 15±15 mmHg (p=0.04) lower after 5 weeks and this persisted for the 8 weeks. Study 2: Subjects given 200 mg b.i.d had a decrease in systolic (p=0.03) and mean BP (p=0.04). BP reached a nadir after 3 weeks when systolic BP was a mean 16 mmHg (p=0.04) lower. BP returned to baseline levels 4 weeks after discontinuation of BH4. Signiﬁcant improvement in FMD was observed in study 1 subjects and those receiving 200mg b.i.d.. In study 2, FMD improved from 3.7±3% at baseline to 7.1±4.9% after 4 weeks of therapy (p=0.016). There was no signiﬁcant change in BP or FMD in subjects given 100 mg b.i.d. and no change in endothelium-independent function with nitroglycerin in any group. There were no serious adverse effects. Conclusions: Oral BH4 at a dose of 200 mg b.i.d. or higher has a signiﬁcant and sustained anti-hypertensive effect in subjects with poorly controlled hypertension. This effect is associated with, and probably secondary to improved endothelial NO bioavailability. 1027-195 Once-Daily Carvedilol Is Effective in Treating Hypertension Michael A. Weber, Domenic A. Sica, Elizabeth A. Tarka, Malini Iyengar, Richard Fleck, George L. Bakris, for the Coreg 367 Investigator Group, GlaxoSmithKline, King of Prussia, PA Background: Carvedilol (carv), twice daily, is an effective antihypertensive agent. We evaluated the effects on blood pressure (BP) of a once-daily (QD) formulation of carv using 24 hour ambulatory blood pressure monitoring (ABPM) in people with essential hypertension. Methods: A double-blind, randomized, placebo-controlled, parallel group, multicenter study was performed comparing 3 doses of carv controlled release (carv CR) with placebo in subjects with hypertension (mean 12 hour daytime diastolic BP [DBP] by ABPM ≥90 but ≤109 mmHg) alone or combined with other therapies. After a Run-in/Washout of up to 4 weeks, eligible subjects were randomized equally to receive carv CR 20 mg QD, 40 mg QD, 80 mg QD, or placebo for 6 weeks. Results: 201 carv CR subjects and 58 placebo subjects had 24 hour ABPM values at both baseline and treatment end. Their mean age was 52 (+ 9.2) years, 34% were female, 77% Caucasian and 18% African American. 41% of subjects remained on background antihypertensive therapy during the study. Mean changes [95% conﬁdence intervals] from baseline in mean 24 hr DBP by ABPM at treatment end were -4.4 [-6.4,-1.6] mmHg, -7.9 [-10.0,-5.2] mmHg and -9.6 [-11.6,-6.8] mmHg for the carv CR 20, 40, and 80 mg treatment groups, respectively compared to a 0.4 mmHg change for placebo. Tukey trend test inferences vs placebo were: p=0.001 for carv CR 80, 40, 20 mg, p<0.0001 for carv CR 40, 20 mg; and p<0.0001 for carv CR 20 mg. Efﬁcacy was maintained at 20-24 hours after the last dose of carv CR: mean changes from baseline DBP were -2.8 mmHg, -5.1 mmHg and -7.3 mmHg for the 20 mg, 40 mg, and 80 mg groups, respectively. Similar responses were demonstrated for systolic BP across the 24 hour period and at the end of the dosing interval. Few adverse events were reported; the most common relevant adverse events were (% on placebo and for the combined carv groups, respectively) headache (6%, 6%) and dizziness (1%, 2%). Conclusions: A new, once-daily formulation of carvedilol demonstrates sustained and effective BP lowering in subjects with essential hypertension in a dose-dependent manner when administered alone or combined with other therapies thus expanding the clinical value of this medication. 1027-196 The Betareceptor Blocker Nebivolol Inhibits Angiotensin II-Induced Aortic and Cardiac Superoxide Formation and Expression and Activity of the Vascular NADPH Oxidase Thomas Münzel, Andreas Daiber, Mathias Oelze, Johannes Gutenberg University, Mainz, Germany Background: Nebivolol (N) is a β1-adrenergic receptor antagonist with vasodilator and antioxidant properties. Since NADPH oxidases are important superoxide (O2 -) sources we studied the effect of N on endothelial function and NADPH oxidase in angiotensin II (Ang-II) induced hypertension. Methods and Results: In male Wistar rats 7d Ang-II infusion (1 mg/kg/d) caused endothelial dysfunction, indicated by a decreased vasodilator potency of acetylcholine in isolated aortic rings, a 2.5 fold increase in O2 - formation in aortic vessels and in NADPH oxidase activity in heart membrane fractions, as detected by lucigenin- (5µM) derived chemiluminescence (LDCL). Staining of aortic sections with the ﬂuorescent dye dihydroethidine showed O2 - formation throughout the vessel wall. Expression of NADPH oxidase subunits was increased in aorta (p67phox 248±42%, rac-1 168±7% of control) and heart membranes (p67phox 259±17%, rac-1 169±26%). In addition, an enhanced ACC_2006_8_VascularDisease.indd 371 1/4/06 5:21:35 PM 372A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n membrane-association of p67phox and rac-1 was detected. Co-treatment with N (10 mg/ kg/d) normalized endothelial function and O2 - formation and prevented upregulation and membrane-association of p67phox and rac-1. Furthermore, in vitro treatment with N but not atenolol or metoprolol induced a dissociation of p67phox and rac-1 as well as a reduction in NADPH oxidase activity assessed in heart membranes from Ang-II infused animals. Conclusions: inhibitory effects of N on vascular NADPH oxidase activity may explain at least in part its beneﬁcial effect on endothelial function in oxidative stress-related cardiovascular diseases such as heart failure and atherosclerosis. 1027-197 Impact of a Novel Hormone Therapy, Drospirenone and 17-beta Estradiol, on Clinic and Ambulatory Blood Pressure in Postmenopausal Women with Hypertension William B. White, Vladimir Hanes, Bertram Pitt, James Neaton, University of Connecticut School of Medicine, Farmington, CT Background: Drospirenone (DRSP), a novel progestin with anti-mineralocorticoid activity, has been combined with 1 mg of 17-ß estradiol (E2) for the treatment of symptoms during menopause. Methods: We assessed the effects of 3 doses of DRSP/E2, E2 alone and placebo on clinic and 24-hour blood pressure (BP) as well as potassium and aldosterone levels in 748 post-menopausal women with stages 1-2 hypertension at baseline and following 8 weeks of double-blind therapy. Results: Patient characteristics (mean age, 56.5 years, 73-77% Caucasian, 13 - 17% African-American) and the clinic (152/95 mmHg) and 24-hour BP (139/83 mmHg) measurements were similar at baseline. Both clinic and ambulatory BPs were reduced signiﬁcantly on DRSP at 2 and 3 mg with E2 compared to placebo, while DRSP 1 mg/ E2 had lesser effects and E2 alone was similar to placebo (Table). Changes in serum aldosterone showed signiﬁcant dose-related increases on DRSP/E2 (Table). Total and LDL cholesterol were lowered signiﬁcantly while triglycerides did not change on DRSP/ E2. Changes in plasma potassium and the incidence of elevated potassium (K+ >= 5.5 meq/L) on DRSP/E2 were not different from placebo or E2 alone. Conclusion: DRSP/E2 at doses of 2 and 3 mg DRSP daily induced signiﬁcant reductions in BP in post-menopausal women without causing clinically important increases in potassium. This attribute could offset some of the untoward cardiovascular events that have been observed in studies of other progestins/estrogens in post-menopausal women. Effects of DRSP/E2 vs E2 and Placebo Parameter 3 mg DRSP/E2 2 mg DRSP/ E2 1 mg DRSP/ E2 E2 only Placebo N 151 149 151 150 147 Change in Clinic BP (mmHg) -13.9*/-8.6* -12.1**/-8.9* -9.6/-6.9† -7.8/- 6.0 -8.7/- 4.8 Change in 24-hour BP (mmHg) -6.4*/-3.8* -4.7**/-2.9** -3.7/-3.1** -1.4/- 1.3 -1.5/- 0.5 Change in Serum K+ (meq/L) 0.06 0.03 -0.02 -0.07 -0.03 Change in Aldosterone (pg/ml) 68.2* 41.0* 13.1 7.5 8.7 * p < 0.001; ** - p < 0.01 ; † - p < 0.05 (DRSP - drospirenone; E2- 17ß estradiol 1 mg) POSTER SESSION 1028 General Topics in Hypertension II Tuesday, March 14, 2006, 12:30 p.m.-4:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 12:30 p.m.-1:30 p.m. 1028-198 Cost-Effectiveness of Chlorthalidone, Amlodipine, and Lisinopril as First-line Treatment for Patients With Hypertension: An ALLHAT Analysis Paul A. Heidenreich, Barry R. Davis, Curt D. Furberg, David R. Lairson, Sara Pressel, Lee Goldman, VA Palo Alto Health Care System, Palo Alto, CA, University of California at San Francisco, San Francisco, CA Objective: To assess the cost-effectiveness (C-E) of ﬁrst-line treatment of hypertension with chlorthalidone as compared with lisinopril or amlodipine we performed an economic analysis of ALLHAT with bootstrap resampling to evaluate uncertainty. Results of Base-Case: Chlorthalidone was the least expensive strategy in 100% of bootstrap replications ($4,822 less than amlodipine, $3,700 less than lisinopril, mean lifetime cost). Due to non-signiﬁcantly lower total mortality, amlodipine provided greater quality adjusted life-years (QALYs) than chlorthalidone in 84% of bootstrap replications (mean 0.1 QALYs) at an incremental C-E ratio of $41,700 per QALY. Lisinopril provided fewer QALYs than chlorthalidone in 55% bootstrap replications (mean -0.007 QALYs) despite a higher cost. Using a societal threshold for C-E ratio of $50,000 per QALY, the optimal initial treatment was amlodipine in 57%, chlorthalidone in 31% and lisinopril in 12% of replications. Sensitivity Analysis: The optimal strategy was sensitive to society’s willingness to pay to gain a quality adjusted year of life (Figure). There was no reasonable combination of assumptions that led to one treatment being preferred in over 90% of bootstrap replications. Conclusion: Therapy initiated with chlorthalidone is less expensive than therapy initiated with lisinopril or amlodipine therapy. However, due to a non-signiﬁcant beneﬁt for total mortality, amlodipine cannot be excluded as a cost-effective alternative. 1028-199 Impact of Gender on the Clinical Beneﬁt of Anti- hypertensive Therapy in Patients With Coronary Artery Disease and Normal Blood Pressure Stephen J. Nicholls, Ilke Sipahi, Paul Schoenhagen, Paul Thompson, David Frid, Harry Shi, Kamlesh M. Thakker, E. Murat Tuzcu, Steven E. Nissen, Cleveland Clinic Foundation, Cleveland, OH, Pﬁzer Global Pharmaceuticals, New York, NY Background: Females with coronary artery disease (CAD) have a high rate of clinical events and hospitalization for angina. Their use of secondary prevention therapies, however, remains suboptimal. It has recently been reported that administration of antihypertensive agents to patients with CAD and blood pressure considered to be within the normal range has a beneﬁcial inﬂuence on both clinical events and the rate of plaque progression. We aimed to determine the impact of gender on the clinical beneﬁt of aggressive blood pressure lowering in these patients. Methods: The Comparison of Amlodipine versus Enalapril to Limit Occurences of Thrombosis (CAMELOT) study randomised 1991 patients with angiographically documented CAD and diastolic blood pressure <100 mmHg to amlodipine 10mg daily, enalapril 20mg daily or placebo for 24 months. The inﬂuence of gender on major adverse clinical events (MACE), hospitalization for angina, coronary revascularization and nonfatal myocardial infarction was determined. Results: Compared with placebo, the incidence of MACE was reduced by 27% (17 v 23%, p=0.03) by amlodipine and 21% (18 v 23%, p=0.09) by enalapril in males (n=1468). This was due to a 39% reduction in hospitalization (8 v 12%, p=0.02) with amlodipine and reduction in revascularization by 28% (13 v 18%, p=0.049) and 30% (13 v 18%, p=0.03) with amlodipine and enalapril respectively. In females (n=523) this beneﬁt appeared to be greater as amlodipine reduced events by 43% (14 v 23%, p=0.03). In contrast, enalapril had no effect on events (25 v 23%, p=0.70). Amlodipine reduced rates of hospitalization by 48% (8 v 14%, p=0.06) and revascularization by 29% (8 v 11%, p=0.36). The rate of nonfatal myocardial infarction was not reduced by use of any antihypertensive in either gender. Conclusion: Initiation of anti-hypertensive therapy with amlodipine in females with CAD and baseline blood pressure considered to be normal was associated with a reduction in clinical events. This further highlights the need for aggressive risk factor modiﬁcation in females with established CAD. 1028-200 Increased Plasma Concentrations of N-terminal Pro Brain Natriuretic Peptide is a More Sensitive Marker of Subclinical Diastolic Dysfunction and Arterial Remodeling in Hypertension: Analytical Performance Comparison With BNP Tomoo Furumoto, Satoshi Fujii, Taisei Mikami, Mamiko Inoue, Keiko Nishihara, Sanae Kaga, Kazutomo Goto, Shogo Imagawa, Kaoru Komuro, Satoshi Yamada, Hisao Onozuka, Akira Kitabatake, Burton E. Sobel, Hiroyuki Tsutsui, Hokkaido University Graduate School of Medicine, Sapporo, Japan, University of Vermont, Burlington, VT Background and Purpose: Concentrations of plasma N-terminal pro brain natriuretic peptide (NT-proBNP) is inversely related to metabolic cardiovascular risk factors and is a valuable prognostic marker of cardiovascular events in arterial hypertension . Whether NT-proBNP levels are connected with diastolic function and arterial function was determined in hypertension. Methods: NT-proBNP was measured in 40 untreated patients with hypertension (mean BP 166/96 mmHg) without heart failure and 20 age and gender matched healthy, controls. Hypertensive patients were studied by pulsed Doppler and color M-mode Doppler echocardiography to evaluate LV diastolic function. Results: Plasma NT-proBNP was signiﬁcantly elevated in patients with hypertension (75.1 ± 75.2 [SD] pg/ml compared with 37.9 ± 38.5 in controls p < 0.05). In hypertensive patients, NT-proBNP values were negatively correlated with the ratio of color M-mode ﬂow propagation velocity to transmitral E velocity (r=-0.33, p<0.05) while those of BNP had no correlation, suggesting that higher plasma NT-proBNP is indicative of subclinical diastolic dysfunction. Moreover, hypertensive patients with higher NT-proBNP values above the mean value in the control group (NT-proBNP > 38 pg/ml) had signiﬁcantly increased brachial intimal-medial thickness (0.36 ± 0.08 mm vs. 0.32 ± 0.05, p < 0.05) and reduced wall stress (112.4 ± 29.5 kPa vs. 142.2 ± 30.8, p < 0.05) compared with those with lower NT-proBNP, suggesting that the reference value of NT-proBNP plasma concentrations in uncomplicated hypertensives is 38pg/ml and higher NT-proBNP levels were associated with favorable remodeling of the peripheral arteries. Conclusions: Elevation of plasma NT-proBNP can be useful to identify subclinical LV diastolic dysfunction and peripheral arterial remodeling in asymptomatic patients with hypertension. ACC_2006_8_VascularDisease.indd 372 1/4/06 5:21:36 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 373A Vascular D isease, H ypertension, and P revention 1028-201 Relationship Between Low-grade Inﬂammation Indices and Target-organ Damage in Patients With Essential Hypertension G. Vyssoulis, A. Zervoudaki, P. Pietri, A. Deligeorgis, G. Antonakoudis, S. Dimitrakopoulos, Th. Gialernios, C. Stefanadis, Athens University, Hippokration Hospital, Athens, Greece Background: Inﬂammation plays a major role in the pathophysiology of hypertension and increases the risk for cardiovascular events. The aim of our study was to examine whether the inﬂammatory markers correlate with target-organ damage in the hypertensive population. Methods: We studied 1472 consecutive patients with untreated, chronic essential hypertension. The average age of patients was 57 years (males 53%). hsCRP, homocysteine and serum amyloid A (SAA) were considered as inﬂammatory markers. Microalbumin was measured in 24-hour urine collection. An echocardiography was performed in all patients and left ventricular mass index (LVMI) was calculated. Microalbuminouria and LV hypertrophy were considered as manifestations of target- organ damage. Results: A step wise multiple regression analysis was performed with microalbuminouria and LVMI being the dependent variables and hsCRP, homocysteine, SAA, WBC, age, gender, glucose, heart rate, systolic and diastolic blood pressure being the independent variables respectively. Microalbuminouria was independently correlated with homocysteine, SAA and WBC (β=0.85 P=0.0001, β=1,99 P=0.0001 and β=0.001 P=0.003 respectively), while no correlation was found with hsCRP (P=NS). LVMI was signiﬁcantly and independently associated with homocysteine, SAA, WBC and hsCRP (β=0.57, β=1.17, β=0.0009, β=1.024, P=0.0001 for all comparisons). Conclusions: Microalbuminouria and LVMI were independently associated with inﬂammatory markers. Low-grade inﬂammation might act as an independent risk factor for target organ damage in hypertensives, thus modifying their prognosis. 1028-202 Effects of Lifestyle Modiﬁcation on Left Ventricular Diastolic Filling and Endothelial Function in Those at Risk for Cardiovascular Diseases Kunihiko Aizawa, J. Kevin Shoemaker, Robert J. Petrella, The University of Western Ontario, London, ON, Canada Background: The purpose of this study was to evaluate the effects of lifestyle (diet and exercise) modiﬁcation on left ventricular diastolic ﬁlling (LVDF), endothelial function and exercise capacity (VO2max) in individuals with either high-normal BP, impaired fasting glucose, or impaired glucose tolerance. Methods: These preliminary ﬁndings are from a randomized trial of Staged Nutrition and Activity Counseling (SNAC) whose plan includes an individually customized Mediterranean style diet with physical exercise vs usual care lifestyle counseling. Fifty two subjects (26 M and 26 F, 54.6 ± 8.8 yrs) have participated in the preliminary analysis of the study cohort. Before, at 8 week, and after 16 weeks of SNAC, measures of LVDF (early and late ﬁlling ﬂow velocities, E/A ratio, isovolumic relaxation time and deceleration time), left ventricular mass, endothelium-dependent (induced by 5-min forearm occlusion) and endothelium-independent (induced by sublingual nitroglycerin administration) vasodilation in the brachial artery assessed using an ultrasound device at rest, and VO2max by exercise treadmill test were determined. Clinic BP using an automated device was also determined. Results: Following 16 weeks of intervention, clinic SBP (127.3 ± 15.0 mmHg vs 133.0 ± 16.4 mmHg) and DBP (79.3 ± 8.8 mmHg vs 83.4 ± 9.8 mmHg) were signiﬁcantly lower than those of baseline (P<.05). VO2max also improved following 16 weeks compared to baseline and at 8 week (34.1 ± 9.0, 36.6 ± 10.2, 39.3 ± 9.5 ml/min/kg, p<.05). These changes were accompanied by the reduction of body weight (92.9 ± 17.0 vs 90.9 ± 16.6 kg) and waist circumference (100.5 ± 13.9 vs 98.1 ± 13.2 cm) following 16 weeks compared to baseline (p<.05). Endothelium-dependent vasodilation tended to be greater at 8 week than baseline; however, it returned to baseline level following 16 weeks. Neither LVDF indices nor endothelium-independent vasodilation changed signiﬁcantly throughout the study period. Conclusion: These preliminary data suggest that our lifestyle modiﬁcation is effective for reducing BP, body weight, and increasing VO2max in those at risk for cardiovascular diseases. 1028-203 Effects of Angiotensin-Converting Enzyme Inhibitors on Interstitial Collagen and QTc Interval In Hypertensive Left Ventricular Hypertrophy Apurva A. Motivala, Thomas Keimig, Karoly Kaszala, Nour-Eddine Rhaleb, Xiao-Ping Yang, Oscar Carretero, Henry Ford Hospital, Detroit, MI Background: Left ventricular hypertrophy (LVH) causes prolongation and heterogeneity in myocardial action potentials represented by a prolonged QTc interval. This prolongation is associated with increased ventricular arrhythmias. Angiotensin-Converting Enzyme inhibitors (ACEi) reduce LVH, QTc, and ventricular arrhythmias in hypertension. N- acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an antiﬁbrotic peptide hydrolyzed by ACE. Whether beneﬁts of ACEi are mediated by a reduction in cardiac interstitial ﬁbrosis due to AcSDKP is unknown. Hypothesis: In this study, we hypothesized that QTc interval normalization by ACEi in hypertension is due to reduction in cardiac interstitial collagen. Methods: To test this, we treated male spontaneously hypertensive rats (SHR) with 1) vehicle + IgG, 2) ACEi + IgG, and 3) ACEi + mAb (monoclonal antibody to AcSDKP). We used age matched male Wistar-Kyoto rats as normotensive controls. Blood pressure was measured weekly. At 12 weeks we recorded ECGs, measured QT intervals from Lead I and corrected them for respective heart rates using the Bazett’s formula. We found increased QTc in the SHR group which was signiﬁcantly normalized with ACEi treatment (279.5±15.6 vs 201.4±9; p<0.005). Addition of Anti-AcSDKP mAb to ACEi had no effect on QTc normalization (238.5±20.7 vs 201.4±9; p=NS). Meanwhile, there was a reduction the LV collagen with ACEi (27.5±5.78 vs 37.66±8.17) which was reversed with anti-AcSDKP mAb (35.59±2.44 vs 27.5±5.78). There was positive correlation between LV mass and QTc (p<0.01) but not between LV collagen content and QTc. Conclusion: Our data suggest that QTc normalization with ACEi treatment in LVH is not due to reduction in cardiac interstitial collagen. Thus in LVH, the anti-arrhythmic beneﬁts of ACE inhibitors may not be signiﬁcantly mediated by their anti-ﬁbrotic effects. 1028-204 The Haemodynamic, and Humoral Mediators of Left Ventricular Diastolic Dysfunction in Essential Hypertension: A Tissue Doppler Imaging Study Dimitris Chatzis, Costas Tsiouﬁs, Efstathios Taxiarchou, Christos Katsaris, Elena Vezali, Apostolis Kakkavas, Christodoulos Stefanadis, Ioannis Kallikazaros, Hippokration Hospital, Athens, Greece Background: Left ventricular (LV) diastolic dysfunction has been linked with adverse cardiovascular prognosis in the setting of essential hypertension (EH). We investigated the potential correlations of haemodynamic and humoral parameters with TDI- detected LV relaxation abnormalities. Methods: 98 consecutive patients (aged 51 years) with newly diagnosed (within the previous 2 years) stage I - II EH and 34 controls matched for age, sex and BMI, underwent 24-h ambulatory blood pressure (BP) monitoring, as well as blood sampling for the determination of brain natriuretic peptide (BNP) levels and metabolic proﬁle. The assessment of LV diastolic function was performed by pulsed TDI, averaging diastolic mitral annular velocities (Em, Am) from 4 separate sites of measurement (LV lateral, septal, anterior and inferior wall). Results: Hypertensives compared to controls exhibited greater ofﬁce systolic BP and diastolic BP (156 ± 13 vs 130 ± 6 mmHg and 101.5 ± 9.5 vs 83 ± 5.2 mmHg, p<0.001 for both cases), as well as increased 24-h systolic BP and diastolic BP (142.5 ± 13 vs 117 ± 5 mmHg and 89 ± 11 vs 70 ± 6 mmHg respectively, p<0.001 for both cases), while the two groups did not differ with respect to their metabolic proﬁle. Moreover, hypertensives compared to controls had signiﬁcantly greater BNP levels (25.7 ± 18.6 vs 17.1 ± 12.3 pg/ml, p<0.05), as well as increased left ventricular mass index (LVMI) and relative wall thickness (RWT) (105.3 ± 26.5 vs 84.3 ± 14 g/m2 and 0.45 ± 0.07 vs 0.4 ± 0.04 respectively, p< 0.001 for both cases). Regarding the TDI data, hypertensives compared to controls exhibited signiﬁcantly lower Em values (8.32 ± 1.6 vs 9.8 ± 1.9 cm/sec, p<0.05) and Em/Am ratio (0.84 ± 0.18 vs 1.07 ± 0.23, p<0.01). In the group of hypertensives, the Em/Am ratio was signiﬁcantly correlated with 24-h systolic BP (r=- 0.342, p< 0.05), 24-h pulse pressure (r=-0.269, p<0.05), RWT (r=-0.254, p<0.05) and BNP plasma levels (r=-0.357, p<0.05). Conclusion: In the early course of EH, the combination of haemodynamic and humoral signals may give rise to LV relaxation abnormalities assessed by TDI. The early recognition of these alterations may contribute to the optimal assessment of hypertensive subjects. POSTER SESSION 1029 Risk Assessment and Stratiﬁcation Tuesday, March 14, 2006, 12:30 p.m.-4:00 p.m. Georgia World Congress Center, Hall B1 Presentation Hour: 12:30 p.m.-1:30 p.m. 1029-205 Cocaine-Related Chest Pain-Utility of TIMI Risk Stratiﬁcation and Effects of Beta Blockers on Outcome Tamam Mohamad, Peter Vaitkevicius, Khaled Bachour, Morhaf Ibrahim, Hossam Higassy, Samir Diab Agha, Luis C. Afonso, Wayne State University, Detroit, MI Background: Cocaine is the most common illicit drug used in patients presenting to emergency departments (ED), accounting for 40 % of drug-related visits and over $ 80 million annually in hospital costs. Data on the potentially deleterious effects of beta-blockers (BB) in this setting is sparse. Our study sought to deﬁne clinical characteristics, utility of TIMI risk stratiﬁcation and the effects of BB in patients presenting with cocaine-related chest pain Methods: Retrospective chart review of patients presenting to an inner-city emergency department with chest pain and positive urine drug screen for cocaine. Results: Three hundred and sixty four charts of patients presenting to the ED and fulﬁlling our inclusion criteria were reviewed. Of 114 (31 %) patients admitted to the hospital, the mean age was 48, 73.4% were male and 90.6% were black. Ninety percent and 26 % reported tobacco and heroin use respectively. Seventy ﬁve percent reported substernal or left precordial chest pain, 62% had nonradiating pain and in 27 % pain radiated to the left arm and or jaw. Troponin-I (TnI) positivity was noted in 7.3 %, more frequently in admitted patients (93 % vs.0.8%, p<0.0001). Fifty one percent of Tn I-positive patients had prior history of coronary artery disease. The TIMI score was the only signiﬁcant predictor for myocardial infarction (MI) progression (p<0.001). Using Minnesota ECG Coding, 16.2 % had left ventricular hypertrophy, 4.1% had ST-segment depression of 1 mm or more, and 50% had prolonged QTc intervals. Patients on BB at presentation were more likely to develop an MI compared to patients who were not (14 % vs. 4.4 %, p<0.01). Continuation or starting BB on admission increased the likelihood of developing MI (23.3% vs.10.7 %, p<0.01). Conclusions: MI is not uncommon in patients with cocaine-associated chest pain. The incidence of MI noted in our cohort using Tn I as the biomarker was 7.3%. Our data identiﬁes and supports the use of TIMI risk score as a tool for predicting MI progression. Although observational in nature, our results conﬁrm for the ﬁrst time the unfavorable effects of BB therapy in patients with cocaine-related chest pain. ACC_2006_8_VascularDisease.indd 373 1/4/06 5:21:36 PM 374A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n 1029-206 Refractory Angina Is Associated With Excessive Chest Pain but Not Excessive Cardiac Mortality Gregory W. Barsness, Ryan J. Lennon, Linda Tesmer, Mayo Clinic College of Medicine, Rochester, MN Background: There is a growing population of patients with ischemic chest pain not amenable to traditional revascularization. Long-term prognosis remains unclear in these patients, with some contemporary series suggesting 1-year mortality of up to 20%. Methods: Clinical characteristics, symptoms and follow-up events were recorded at baseline visit and at 6 month intervals in 200 consecutive patients with ischemic coronary disease and CCS class 3 or 4 angina consenting to follow-up. All patients were on optimal medical therapy and deemed unrevascularizable by a referring provider due to comorbidities and/or unfavorable coronary anatomy. Results: Patients were elderly (median 68 yrs), primarily men (80%), with a history of diabetes (44%), hypertension (76%), tobacco use (54%), heart failure (20%), MI (58%), and prior PCI (67%), CABG (83%), TMR (5%) and/or heart transplant (1%). Mean LVEF was 50%. Observed 1-year events included MI (10%), CVA (1%), urgent revascularization (11%) and death (5.5%). There were 27 deaths during 3 year follow-up (median, 25th, 75th: 1.9, 5), with a 5-yr KM mortality estimate of 23% (10% cardiac). Conclusion: Patients with symptomatic coronary artery disease deemed to be unrevascularizable are at high risk for subsequent non-fatal coronary events. However, the long-term cardiac mortality in this cohort remains low (2%/yr) even in the setting of advanced age and severe comorbidities. Ongoing efforts to identify safe and effective measures of symptom relief are required. 1029-207 Fragmented QRS (rsr` Pattern and Its Variants; QRS duration <120 ms) Predicts Signiﬁcant Cardiac Events and Mortality in Patients Undergoing Stress Testing Hicham Ziad El Masry, Mithilesh Kumar Das, Krannert Institute of Cardiology, Indianapolis, IN Background: Fragmented QRS (fQRS) without typical bundle branch block represents terminal conduction delay and is associated with signiﬁcant perfusion abnormality and myocardial scar on nuclear stress imaging. However, the prognostic signiﬁcance of fQRS (ﬁgure) is unknown. We, therefore, postulated that fQRS is an independent predictor of cardiac events and all cause mortality in patients with known or suspected coronary artery disease. Methods: We conducted a retrospective study of 1026 consecutive patients who underwent nuclear stress testing at a university afﬁliated VA hospital. We reviewed the 12-lead EKG for fQRS including RSR`or any of its variants (rSr`, RSr`, rSR, notched or multiphasic R wave, and notched or multiphasic S wave) in the absence of typical bundle branch block (QRS <120 ms) in any 2 contiguous leads corresponding to a major coronary artery territory. Results: 1,000 (mean age: 65.5±11.5; male: 96.9%) had adequate nuclear images for interpretation and 273 pts were identiﬁed to have fQRS. Over a median follow up period of 69±23 months (±1 SE), cardiac events (myocardial infarction [ST elevation and non-ST elevation], unstable angina, hospitalization for cardiac causes and need for revascularization) and mortality were signiﬁcantly higher in patients with fQRS than in patients without fQRS (p = 0.001 for events; p= <0.014 for death). Conclusions: fQRS was associated with signiﬁcant increased risk for cardiac events and all cause mortality in patients undergoing stress test. 1029-208 Fragmented QRS on 12-lead ECG Represents Increased Cardiac Events and Mortality in Diabetic Patients With Abnormal Myocardial Perfusion Scan Hicham Ziad El Masry, Mithilesh Kumar Das, Krannert Institute of Cardiology, Indianapolis, IN Background: Fragmented QRS (fQRS) without typical bundle branch block (BBB) represents terminal conduction delay and is associated with signiﬁcant perfusion abnormality and myocardial scar on nuclear stress imaging. Diabetics have higher incidence of asymptomatic myocardial perfusion defects and asymptomatic coronary events, therefore, we postulate that fQRS (ﬁgure) is a predictor of mortality and coronary events. Methods: ECG and myocardial perfusion scan of 1026 pts, who underwent nuclear stress testing at VA hospital was reviewed. The fQRS was deﬁned as various RSR` patterns (rSr`, RSr`, rSR, notched R wave, notched S wave) in the absence of typical BBB in any 2 contiguous leads corresponding to a major coronary artery territory. Results: Only 1001 (mean age: 65±11 years; male: 96.9%: median follow up: 58±22 months), had adequate nuclear imaging, 282 pts were diabetic, and 273 pts were identiﬁed to have fQRS (DM:36.5%; NoDM:27.3%, p=0.005). Myocardial infarction, need for revascularization and mortality was signiﬁcantly higher in pts with diabetes and fQRS (p<0.001) as compared to patients without diabetes and fQRS. These endpoints were independent of the results of myocardial perfusion scan (coronary events: p=0.001, Mortality: p<0.02). Conclusions: Diabetics have a signiﬁcantly higher incidence of fQRS, which may represent silent coronary events. fQRS is associated increased risk of coronary events and mortality which is independent of the results of nuclear perfusion imaging. 1029-209 Cardiovascular Events in Clinical Trials Involving Over 41,000 Patients Evaluating the Cyclooxygenase-2 Inhibitor Celecoxib William B. White, Jeffrey S. Borer, Philip B. Gorelick, Sharon X. Pan, Christine R. West, Ethan Weiner, Kenneth Verburg, University of Connecticut School of Medicine, Farmington, CT, Pﬁzer, Inc, Ann Arbor, MI Background: To determine whether the COX-2 inhibitor, celecoxib, affects cardiovascular (CV) risk, we analyzed the incidence of CV events for celecoxib, placebo, and NSAIDs in the clinical trial database for celecoxib using deﬁned endpoints of nonfatal myocardial infarction, stroke, and CV death. Methods: Patient data were derived from studies in arthritis, back pain, and Alzheimers ACC_2006_8_VascularDisease.indd 374 1/4/06 5:21:37 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 375A Vascular D isease, H ypertension, and P revention disease. The meta-analysis included 7,462 patients exposed to celecoxib, 200 to 800 mg daily, for 1,268 patient-years compared to 4,057 patients treated with placebo for 585 patient-years, and 19,773 patients treated with celecoxib, 200 to 800 mg daily, for 5,651 patient-years compared to 13,990 patients treated with nonselective NSAIDs [diclofenac, ibuprofen, naproxen) for 4,386 patient-years. The CV events were evaluated by a 3-member CV endpoint committee (WBW, JB, PG) blinded to treatment group and study (adjudicated events). Results: The incidence rates of the combined CV events were not signiﬁcantly different between celecoxib and placebo or between celecoxib and the NSAIDs (Table). Event rates were similar for adjudicated and non-adjudicated data. Dose of celecoxib, use of aspirin, presence of CV risk factors, and treatment indication (OA vs RA vs other) did not alter these results. Conclusions: These analyses fail to demonstrate an increased CV risk of celecoxib relative to placebo in this database and demonstrate a comparable rate of CV events with celecoxib treatment versus the nonselective NSAIDs. CV Events in Celecoxib Trials Event Assessment Celecoxib CV Events Comparator CV Events RR (95% CI); P value Non-Adjudicated Events/N Events/100 pt-yrs Events/N Events/100 pt-yrs Placebo-controlled 23/7462 1.81 8/4057 1.37 1.26 (0.57, 2.80) p=0.57 NSAID-controlled 57/19773 1.01 54/13990 1.23 0.86 (0.59, 1.26) p=0.44 Adjudicated Placebo-controlled 18/7462 1.42 7/4057 1.20 1.11 (0.47, 2.67) p=0.81 NSAID-controlled 54/19773 0.96 49/13990 1.12 0.90 (0.60, 1.33) p=0.59 1029-210 Use of Anti-Inﬂammatory Medications in Patients at Risk for Cardiovascular Diseases Leonardo Tamariz, Yves Jeanty, Hermes Florez, Alan Bakst, Ana Palacio, University of Miami - Humana Health Services Research Center, Miami, FL, TAP Pharmaceuticals, Lake Forest, IL Background: Selective cyclo-oxygenase 2 (Cox-2) inhibitors and non-steroidal anti- inﬂammatory drugs (NSAID) have received intensive scrutiny because of the increased incidence of cardiovascular events. The purpose of this report is to determine the patterns of use of anti-inﬂammatory medications by cardiovascular risk before Cox-2 inhibitors were withdrawn from the market. Methods: We analyzed cross-sectional claims data of a large health beneﬁts company. Subjects were selected from the database between the dates of April 1and June 30, 2003 if they had ﬁlled a prescription for NSAID or Cox-2 inhibitors. Subjects were identiﬁed as having higher cardiovascular risk if they had at least one of the following ICD-9 or NDC codes: hypertension, chronic atrial ﬁbrillation, dyslipidemia, diabetes, or estrogen replacement therapy. Results: We identiﬁed 27,827 patients using anti-inﬂammatory medications. Of those, 72% used NSAID and 28% used Cox-2 inhibitors. NSAID users, when compared to Cox-2 inhibitor users, were older (62.6±13.7 vs. 58.6±12.3, p<0.01) and more likely to be female (71% vs. 39%, p<0.01). There were no differences in the frequency of CV risk factors or the mean cardiovascular risk score was similar in all medication users (0.6±0.4). Cox-2 inhibitors were more commonly used in patients with atrial ﬁbrillation and in those on hormone replacement therapy, while NSAID were commonly used in patients with hypertension and diabetes. In logistic regression models adjusted for gastrointestinal risk, signiﬁcant predictors for NSAID use were cardiovascular risk (OR 0.92; 95% CI 0.86- 0.98), age (0.96; 95% CI 0.95-0.96), male gender (1.11; 95% CI 1.04-1.18) and Medicare/ Medicaid insurance. Signiﬁcant predictors for Cox-2 inhibitor use were cardiovascular risk (OR 1.16; 95% CI 1.10-1.24), age, Medicare/Medicaid insurance and male gender. Conclusions: In a large managed care population, Cox-2 inhibitors were more frequently used in patients at risk for coronary artery disease when compared to NSAID. Cox-2 inhibitors were used in younger female patients with higher thrombotic risk (hormone replacement and atrial ﬁbrillation). 1029-211 Patterns and Predictors of Aspirin Use Among Patients on Chronic Anti-Inﬂammatory Drugs Ana Palacio, Hermes Florez, Yves Jeanty, Alan Bakst, Leonardo Tamariz, University of Miami - Humana Health Services Research, Miami, FL, TAP Pharmaceuticals, Lake Forest, IL Background: The efﬁcacy of aspirin in primary and secondary prevention is well established. However, use of chronic non-steroidal anti-inﬂammatory drugs may impact aspirin use. We evaluated the hypothesis that aspirin will be underused in patients taking chronic anti-inﬂammatory drugs even in the presence of coronary artery disease (CAD) or CAD equivalents, like diabetes and stroke. Methods: We administered a telephonic survey to a sample of consecutive members of a large health beneﬁts company. The sample was selected from a population of patients who used anti-inﬂammatory drugs. The survey consisted of 10 close-ended questions divided into several domains: use of aspirin, reasons for use or lack of use, self report of cardiovascular risk factors and dosage. We linked the survey to the database and used ICD-9 codes to identify cardiovascular risk factors in the 12 months prior to the administration of the survey. Results: The sample consisted of 1,250 members, 48% of whom were aspirin users (49% for primary prevention of myocardial infarction and 34% for stroke prevention). When compared to non-users, aspirin users were older (67.5±11.4 years vs. 65±12.1 years, p<0.01), less likely to be females (45% vs. 55%, p<0.01), more likely to have had myocardial infarction (62% vs. 38%, p<0.01), and less likely to be smokers (40% vs. 60%, p=0.05). In logistic regression models, history of myocardial infarction (OR 1.59; 95% CI 1.04-2.43) as well as age and male gender remained as signiﬁcant predictors for aspirin use, while stroke and diabetes were not associated with aspirin use. Gastric discomfort (19%) and lack of indication (28%) were the main reasons for not using aspirin. This was particularly relevant since 6% of the patients who reported lack of indication had a previous cardiovascular event (stroke or myocardial infarction) and 27% had diabetes. Conclusions: Advanced age, male gender, and a prior history of myocardial infarction predict the use of aspirin in this managed care population. Since stroke and diabetes were not associated with aspirin use in this population of chronic anti-inﬂammatory users, there is a need for education on the beneﬁts of aspirin in these CAD equivalent conditions. 1029-212 Intensive Multicomponent Smoking Cessation Intervention Decreases Mortality in Hospitalized High- Risk Cardiac Smokers Syed M. Mohiuddin, Aryan N. Mooss, Claire B. Hunter, Timothy Grollmes, David A. Cloutier, Daniel E. Hilleman, Creighton University Cardiac Center, Omaha, NE Purpose: To compare an intensive multi-component smoking cessation intervention (ISI) against usual care (UC) in hospitalized high risk smokers with acute cardiovascular disease (acute coronary syndrome, decompensated heart failure, coronary artery revascularization). Methods: A total of 209 smokers were randomized to ISI (n = 109) or UC (n = 100). All smokers received counseling and written educational materials prior to hospital discharge. ISI consisted of a minimum of 8 weeks of behavior modiﬁcation counseling and individualized pharmacotherapy. Smoking status was conﬁrmed biochemically (expired CO) at 3, 6, 12, and 24 months after randomization. Subjects randomized to ISI who relapsed were re-treated as necessary. Outcomes included both point-prevalence (PP) and continuous abstinence (CA) smoking cessation rates, hospitalizations and mortality. Results: At baseline, the two treatment groups were not signiﬁcantly different with the exception of a higher number of cigarettes smoked per day in the ISI group (26.2 ± 14.5) compared to the UC group (22.1 ± 11.5) (p = 0.017). Adjunctive pharmacotherapy was used more commonly in the ISI group (78%) compared to the UC group (17%)(p < 0.0001). At each follow-up interval, both PP and CA smoking cessation rates were signiﬁcantly greater in the ISI vs UC groups. At 24 months, CA smoking cessation rates were 45% in ISI and 11% in UC (p < 0.0001). Over the two-year follow-up, 41 patients in the UC group were hospitalized compared to 25 patients in the ISI group (RRR 44.1%; 95% CI 16%-63%; p = 0.007). All-cause mortality was 2.8% in the ISI group and 12.0% in the UC group (RRR 77.1%; 95% CI 27%-93%; p = 0.014). Conclusion: An intensive multicomponent smoking cessation intervention in high risk hospitalized smokers with acute cardiovascular disease is associated with higher smoking cessation rates and reductions in hospitalization and all-cause mortality. 1029-213 Prognostic Value of Serum Gamma-Glutamyl Transferase Activity in Coronary Artery Disease Michele Emdin, Aldo Paolicchi, Claudio Passino, Alfonso Pompella, Luigi Donato, CNR Institute of Clinical Physiology, Pisa, Italy Background: Serum gamma-glutamyl transferase activity (γ-GT), responsible in presence of glutathione and iron of oxidative processes in the extracellular milieu, has been documented as an independent risk factor for cardiac mortality in coronary artery disease and in unselected populations. γ-GT activity has been documented in coronary atherosclerotic plaques colocalized with LDL lypoprotein, which are oxidized in its presence. Methods: The purpose of this prospective study was to determine the relative prognostic value of γ-GT in 474 consecutive patients with angiographically documented coronary artery disease in respect of C-reactive protein (CRP) levels, and other humoral and clinical recognized risk factors, using cardiac mortality as end-point. Results: γ-GT showed an independent prognostic value beyond known established risk factors, as well as the extent of coronary atherosclerotic disease, the left ventricular ejection fraction, the age of the patients, and, among humoral risk factors, the blood glucose level, serum LDL level, and the CRP assay, which at the multivariate analysis were the only independent predictors of cardiac death, together with γ-GT. The relation between γ-GT levels and cardiac events remained signiﬁcant after adjustment for possible confounders, including alcohol consumption. At a 3-year follow-up, cardiac mortality was 9% in patients with γ-GT >25 U/L versus 3.5% in those with γ-GT <25 U/L (P=0.028). Excess mortality in patients with higher γ-GT, were concentrated in the ﬁrst two years of follow-up (P=0.014). At 3-year follow-up, no one died among patients with lower CRP, serum LDL, glucose and γ-GT, or positivity for only one of these factors. The association of three or more risk factors among higher γ-GT, CRP, blood glucose, or LDL identiﬁed a subgroup of 145 patients with a highest risk of cardiac death at 3 years (15.2%, versus only 0.3% in the subset of 329 patients with lower values of γ-GT, CRP, and LDL, P= 0.0002). Conclusion: γ-GT serum activity is conﬁrmed as independent cardiac risk factors in ischemic patients with established coronary atherosclerosis, its prognostic value resulting additive to LDL, glucose, and CRP. 1029-214 Pregnancy Complications as Risk Factors for Coronary Artery Disease Mimi S. Biswas, Monique Chireau Chireau, Emily Honeycutt, Haywood Brown, L Kristin Newby, Lori A. Bastian, Duke University Medical Center, Durham, NC, Durham Veterans Admistration Medical Center, Durham, NC Background: Adverse pregnancy outcomes have been associated with future maternal cardiovascular disease in population studies, but their risk for the development of CAD has not been studied. Methods: We performed a retrospective cohort study merging data from the Duke University Perinatal and Health Services Outcomes Database (PHSOD) , and the Duke Information System for Cardiovascular Care (DISCC). The 42,263 patients in the PHSOD were queried in the DISCC database, yielding 415 patients. Logistic regression modeled predictors of CAD, using accepted clinical cardiac risk factors as well as pregnancy complications, including ICD-9 codes for abruption, preeclampsia, preterm birth, gestational diabetes, in-utero fetal demise, small- and large-for gestational age, ACC_2006_8_VascularDisease.indd 375 1/4/06 5:21:37 PM 376A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n oligohydraminos, post-partum hemorrhage, stillbirth, and twins. Results: Median age at delivery was 28 years [23,33 IQR] and 41 years [35, 47 IQR] at catheterization. 33% of women were white, 65% black. While black women delivered younger (median 26 vs. 29 yrs old, p<0.001), age at ﬁrst documented MI after pregnancy (43 years [37,48 IQR]) did not vary by ethnicity, yet black women were older at their ﬁrst documented cardiac catheterization (median 42 vs. 38 yrs old, p<0.001). Pregnancy complications occurred in 214 patients. Women with pregnancy complications were more likely diabetic, with hypertension, unstable angina, and CAD on catheterization (35% vs. 24% p 0.02). In univariate analysis, Caucasian race, diabetes, hypertension, peripheral vascular disease, cerebrovascular disease, smoking, hyperlipidemia, gestational diabetes and any pregnancy adverse outcome were associated with CAD. In multivariate analysis, Caucasian race (OR 2.7 [1.38-5.16], diabetes (OR 2.0 [0.99-3.99], and hyperlipidemia (OR 3.8 [1.97-7.32]) were associated with CAD, with incremental model improvement with any adverse pregnancy outcome (OR 2.6 [1.29-5.10]). Conclusions: History of pregnancy complications is associated with risk for CAD in this young cohort. Prospective studies are needed in this area. Women identiﬁed as having increased risk for CAD based on pregnancy complications may beneﬁt from early preventive interventions. ORAL CONTRIBUTIONS 853 Endothelial Dysfunction: Causes, Cardiovascular Risk and Treatment Tuesday, March 14, 2006, 2:00 p.m.-3:30 p.m. Georgia World Congress Center, Room B406 2:00 p.m. 853-3 Endothelial-dependent vasodilation and Prognosis in Postmenopausal Women Rosario Rossi, Annachiara Nuzzo, Giorgia Origliani, Maria G. Modena, University of Modena and Reggio Emilia, Modena, Italy, Centro “Bene Essere Donna”. Azienda Policlinico di Modena, Modena, Italy Background: Cardiovascular events are the primary cause of death and inability in all industrialized countries. Conventional cardiovascular risk factors (cigarette smoking, hypercholesterolemia, hypertension and diabetes) fail to explain nearly 50% of cardiovascular events. This study examines the association between endothelial- dependent vasodilation and cardiovascular events in a population of initially asymptomatic postmenopausal women. Methods: We conducted a prospective study on 2,159 postmenopausal women, aged 54 ± 5 years (range: 48-60 years). Endothelial function was measured as ﬂow-mediated dilation (FMD) of the brachial artery, using high-resolution ultrasound. The lenghts of the follow-up was 42 ± 12 months (range: 6-60 months). Information on the occurrence of cardiovascular events was collected and conﬁrmed by use of medical records and death certiﬁcates. Results: During observation, 81 events were recorded: 45 TIA; 18 ischemic stroke; 8 acute myocardial infarction; 8 hospitalization for coronary revascularization; 2 cardiac- related deaths. Among patients with events, FMD resulted 3.4% ± 1.7[SEM], compared with 9.5% ± 1.9[SEM] recorded in women event-free (p<0.0001). The events rate among patients in the lowest tertile of FMD (FMD < 4.5%) was greater than the combined event rate observed in the other 2 tertiles (women in the lowest tertile accounted for 44 events [54.3% of total events]: 30 TIA/45, 9 stroke/18, 2 deaths/2 and 3 MI/8). The relative risk (RR) for women in the lowest tertile was 6.77 (Crude. 95% CI: 5.44-12.5) vs. women with FMD > 8.3% (highest tertile, reference): The RR, adjusted for age and conventional risk factors, resulted 4.55 (95% CI: 3.55-6.32). When added to age and other risk factors, the presence of FMD% contributed signiﬁcantly to model predicting cardiovascular events (Likelihood Ratio �2 change: 9.16; p<0.0001) Conclusions: In postmenopausal women, knowledge of FMD% provides incremental information regarding the risk of developing cardiovascular events in addition to that deﬁned by conventional cardiovascular risk assessment. 2:15 p.m. 853-4 Periodontal Disease and Endothelial Function Francesco D’Aiuto, Luigi Nibali, Mohamed Parkar, Jean Suvan, Donna Moskal, Ann E. Donald, Claire Storry, Patrick Vallance, Maurizio S. Tonetti, John E. Deanﬁeld, Eastman Dental Institute, London, United Kingdom Background: Extrinsic inﬂammation may impair vascular function and epidemiological evidence suggests a link between periodontitis and cardiovascular outcomes. Methods: We performed a double blind randomized controlled clinical intervention trial of the effects of non pharmacological periodontal treatment on endothelial function (EF). 120 subjects suffering from severe periodontitis (60 males, mean age 48±7 years) were randomized to a standard (SPT, N=59) or intensive (IPT, N=61) course of periodontal therapy. EF assessed by brachial artery Flow Mediated Dilatation (FMD) was studied before and 1, 7, 30, 60 and 180 days after therapy together with inﬂammatory [C-reactive Protein (CRP), Interleukin-6 (IL-6)], endothelial [s-Eselectin (s-Es), von Willebrand Factor (vWF)] and coagulation bio-markers (PAI-1, t-PA) at each point. Results: Within one day of IPT, FMD signiﬁcantly decreased (2.2±0.4 % mean difference compared to baseline, P<0.0001) and was associated with an acute inﬂammatory response (13.7±1.7 mg/L CRP mean increase, P<0.0001, 8.1±1.0 pg/ml IL-6 mean increase, P<0.0001) increased soluble endothelial markers (18 to 20% median increase in s-Es, P=0.023 and vWF, P<0.001 respectively) and a pro-coagulant state (5.2±2.3 ng/ml PAI-1 mean increase, P=0.029). Over the next 6 months however EF improved progressively in the IPT group so that by 180 days EF was signiﬁcantly better than baseline (1.0±0.3% mean increase, P=0.002). EF and plasma endothelial markers improved in the IPT versus SPT subjects at 60 (mean differences of -0.9±0.4% in FMD, P=0.023 and 31.4±25.7 ng/ml in s-Es, P=0.024) and 180 days (mean differences of -2.0±0.4% in FMD, P<0.0001 and 30.7±25.7 ng/ml in s-Es, P=0.034). These acute and long term changes were not observed in the SPT patients. Conclusions: Extrinsic inﬂammation from periodontal disease is associated with vascular dysfunction. This resolves rapidly when the inﬂammatory stimulus is removed by IPT. Periodontal therapy represents a unique in vivo model to study the impact of inﬂammation on vascular function. Periodontitis management may have signiﬁcant clinical beneﬁts on atherosclerotic outcomes. 2:30 p.m. 853-5 Atrial Fibrillation Is Associated With Reversible Impairment of Endothelial Function Evangelos A. Zacharis, Emmanuel I. Skalidis, Dimitrios K. Tsetis, Kostas Pagonidis, Emmanuel G. Manios, George F. Diakakis, Michael I. Hamilos, Panos E. Vardas, Heraklion University Hospital, Heraklion, Greece Background: Beat-to-beat variation in blood ﬂow dynamics during atrial ﬁbrillation (AF) has been associated with evidence of endothelial dysfunction. The aim of the present work was to conﬁrm endothelial dysfunction in patients with AF, as well as to test the hypothesis that endothelial dysfunction is reversible upon restoration of the normal sinus rhythm. Methods. Endothelium-dependent (ﬂow-mediated dilatation, FMD) and endothelium- independent (nitroglycerin-mediated dilatation, NMD) vasodilator function of the brachial artery were measured by using high-resolution ultrasound in 46 patients with persistent AF who were scheduled for internal electrical cardioversion and in 21 control subjects. In the 19 patients, who remained in sinus rhythm following cardioversion these measurements were repeated after 24hours and one month. Results: Compared with control subjects, patients showed lower FMD during AF (8.0 ± 3.9% vs 12.7 ± 3.1% respectively; p<0.05) and comparable NMD (17.1 ± 3.9% vs 15.5 ± 3.1% respectively; p=NS). Sinus rhythm restoration was associated with higher FMD both at 24 hours and at one month (10.6 ± 4.6% and 13.6 ± 5.3% respectively; p<0.05 for both compared to values during AF). In contrast, NMD was not signiﬁcantly altered at 24 hours and at one month after sinus rhythm restoration (17.2 ± 4.0% and 16.9 ± 4.1% respectively; p=NS for both compared to values during AF). Conclusions: AF is associated with an impairment of endothelial function that improves after SR restoration, indicating an independent contribution of AF to atherosclerosis. 2:45 p.m. 853-6 Endothelial Dysfunction Accelerates Future Hypertensive Evolution and Causes Excess of Fatal Events Tatsuaki Murakami, Hiromasa Kokado, Fukui Cardiovascular Center, Fukui, Japan Background: Hypertension and endothelial dysfunction (ED) are thought to affect atherosclerotic processes, but we know little about the relationship between ED and evolutional mechanism of hypertension. This study assessed hypothesis that ED accelerates hypertensive evolution (HTE) and affects longevity of the patients. Methods: ED was graded by ultrasonic measured reactive changes in lumen diameter of brachial artery after transient forearm occlusion (FMD) in consecutive 518 patients with suspected coronary artery disease. The enrolled patients were categorized into 3 groups according to the values of FMD, and we prospectively followed-up their HTE and fatal events for 36 months or more. HTE was deﬁned as no less than two stage upgrade of hypertension proposed by JNCVI or new administration of an antihypertensive agent. Results: For a mean follow-up period of 57 months with 100% follow-up, the patients with severe endothelial dysfunction (FMD<4%; Group-L, n=174) more frequently developed HTE compared to Group-M with mild endothelial dysfunction (4%≤FMD<8%, n=171) plus Group-H with preserved endothelial function (FMD 8% or more), [44(25.2%) versus 17(9.9%) plus 9(5.2%), p<0.001, by Kaplan-Meier analysis] and fatal outcome [15(8.6%) versus 4(2.3%) plus 2(1.2%), p<0.001]. Cox proportional hazard model analysis showed that severe endothelial dysfunction was the predictor for HTE (odds ratio=2.87, 95%conﬁdential interval; 1.73-4.77, p<0.001) and the only predictor for future cardiovascular death (odds ratio=10.34, 95%conﬁdential interval; 1.26-72.25, p=0.022) and all-causal death (odds ratio=5.87, 95%conﬁdential interval; 1.12-52.34, p=0.009). Conclusions: These results indicate that endothelial dysfunction increases hypertensive evolution and mortality of the patients. 3:00 p.m. 853-7 Coronary Flow Reserve Is a Poor Marker of Coronary Microvascular Response Narbeh Melikian, Martyn R. Thomas, Mark T. Kearney, Bernard DeBruyne, Ajay M. Shah, Philip A. MacCarthy, King’s College School of Medicine at Guy’s King’s and St Thomas Hospitals, London, United Kingdom, OLV Cardiothoracic Center, Aalst, Belgium Background Coronary microvascular function (Mcor) has important emerging implications in clinical diagnosis, risk stratiﬁcation and prognosis of patients and its comprehensive assessment requires information on both endothelium-dependent and -independent coronary responses. Coronary ﬂow reserve (CFR) is a commonly used index for Mcor and is derived from the ratio of maximal hyperaemic (often achieved with a non-speciﬁc vasodilator, adenosine) to basal coronary ﬂow. We hypothesized that adenosine derived CFR may not adequately interrogate the endothelium-dependent component of the coronary microvasculature. ACC_2006_8_VascularDisease.indd 376 1/4/06 5:21:38 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 377A Vascular D isease, H ypertension, and P revention Methods & Results A thermodilution technique (using intracoronary pressure wire) was employed to sequentially compare CFR (hyperaemia achieved with adenosine 140µg/ kg/ml via femoral vein) with % change in coronary ﬂow in response to the endothelial agonist substanceP (endothelium dependent response - 20pmol/min intracoronary infusion for 2 minutes) in 56 unobstructed coronary arteries of patients undergoing angioplasty to an adjacent vessel. Mean (±SD) age of patients studied was 65±10 years (55% male, 18% diabetic). Mean CFR was 2.9±1.3 and substanceP induced change in blood ﬂow 22.2±17.4%. There was no correlation between CFR and coronary endothelial response (r=0.1, p=0.2). We then individually studied the relationship between CFR and coronary endothelial response, and established clinical markers of endothelial dysfunction. There was a strong correlation between coronary endothelial response and patient’s Framingham Risk Score (FRS - a surrogate marker for cardiovascular risk factor clustering; hence an indirect measure of endothelial dysfunction - r= -0.5, p<0.0001), but no correlation between CFR and FRS (r=0.01, p=0.7). Diabetic patients had signiﬁcantly greater coronary endothelial dysfunction than non-diabetics (p=0.001). CFR was not inﬂuenced by diabetes in this patient cohort (p=0.4). Conclusions Adenosine derived CFR may not adequately interrogate the endothelium- dependent component of the coronary microvasculature. We propose that information on both CFR and coronary endothelial function are required to comprehensively assess Mcor. 3:15 p.m. 853-8 Erythropoietin Therapy Improves Vascular Dysfunction in Pre-dialysis Chronic Renal Failure Patients: A Novel Strategy for Atherosclerosis Prevention Angela YM Wang, Ping Chook, Siu F. Lui, Kai M. Chow, Philip KT Li, John E. Sanderson, Kam S. Woo, The Chinese University of Hong Kong, Hong Kong, Hong Kong Background: Chronic renal failure (CRF), is associated with cardiovascular diseases. Erythropoietin (EPO) therapy improves heart failure and quality of life, but its beneﬁt in atherosclerosis prevention remains unproven. Methods: 66 CRF patients (28 males, 38 females) (serum creatinine 150-700µmol/l) with no known cardiovascular disease and hemoglobin (Hb) < 11g/dl were randomized to receive weekly subcutaneous injection of EPO 4000 units for 48 weeks (n=32), dose uptitrating to normalize Hb levels, or to standard conservative medical treatment (CONTROL n=34). Flow-mediated dilation (FMD) of brachial artery and carotid intima- media thickness (IMT) were measured. Results: Their mean age was 51.6±13.7 years. Blood Hb signiﬁcantly increased in EPO group (P<0.001), total cholesterol (TC) decreased signiﬁcantly in control group, and creatinine further deteriorated in both groups (P<0.001), but there were no signiﬁcant changes in their blood pressures. FMD increased signiﬁcantly (P<0.01) after EPO treatment, associated with mild improvement in carotid IMT (P<0.05). On multivariate linear regression analysis, improvement in FMD is related to changes in Hb (ß=0.81; P=0.004), independent of changes in creatinine, TC and EPO treatment (R²=0.36; F value =7.3; P<0.001). Conclusions: Correction of hemoglobin with EPO in predialysing CRF is associated with signiﬁcant improvement in vascular function, promoting a new strategy for atherosclerosis prevention. Changes after EPO Therapy Control EPO Baseline 48 weeks Baseline 48 weeks Haemoglobin (g/dl) 10.0±1.0 9.2±1.5*** 10.1±0.7 13.4±0.9*** Creatinine (umol/l) 376.5±138.5 493.8±209.4*** 375.9±95.5 529.6±228.6*** TC (mmol/l) 5.1±1.3 4.6±1.1** 4.9±1.1 4.7±1.5 FMD (%) 5.6±1.6 5.8±1.6 5.3±1.9 6.4±1.5** IMT (mm) 0.70±1.51 0.69±1.64 0.74±1.54 0.72±1.54* P<0.05; **P<0.01: ***P<0.001 ORAL CONTRIBUTIONS 854 Inﬂammation and Vascular Disease Tuesday, March 14, 2006, 2:00 p.m.-3:30 p.m. Georgia World Congress Center, Room B314 2:00 p.m. 854-3 May an Acute Coronary Syndrome Occur in the Absence of Inﬂammation? Pedro Monteiro, Susana Costa, Francisco Goncalves, Maria Emilia Morais, Lino Goncalves, Mario Freitas, Luis A Providencia, Coimbra University Hospital, Coimbra, Portugal Background: Acute coronary syndromes (ACS) are usually characterized by inﬂammatory cascade activation. C-reactive protein (CRP) is the most widely used marker of this cascade. But are inﬂammatory markers always elevated in ACS? Aim: To determine which parameters could predict an ACS without inﬂammatory activation. Methods: We studied 338 consecutive patients admitted for ACS in a single centre between May/2004 and September/2005. Patients with evidence of infection or chronic inﬂammatory diseases were excluded. The remaining patients were divided in 2 groups: group A - patients with normal CRP (n=34) and group B - patients with high CRP levels (n=304). Both groups were analysed regarding demographics, clinical, therapeutic and prognostic parameters. Results (table 1): Group A patients were younger and more frequently treated with aspirin and statins before hospital admission. Their infarctions were smaller (as evaluated by peak enzymes release) resulting in a better left ventricular (LV) ejection fraction. Conclusions: In ACS, a small percentage of patients have no inﬂammatory cascade activation. Normal CRP, probably related to previous use of drugs with known anti- inﬂammatory activity, predicted less myocardial necrosis and hence better LV function. Table 1- results A (n=34) B (n=304) p Age (years) 61.0+/-11.0 66.2+/-12.8 0.023 Male (%) 76.5 67.8 n.s. Previous aspirin (%) 67.9 44.5 0.021 Previous statins (%) 64.3 35.7 0.004 LV ejection fraction (%) 55.4 49.6 0.034 cTnI (ng/ml) 5.4+/-15.2 34.1+/-56.9 0.004 CKMB mass (ng/ml) 17.1+/-33.6 112.6+/-203.7 0.008 2:15 p.m. 854-4 Diabetes Mellitus Type 2 Predisposes to Increased Culprit Plaque Inﬂammatory Activation in Patients With Coronary Artery Disease. Eleftherios Tsiamis, Konstantinos Toutouzas, Virginia Markou, Maria Drakopoulou, Manolis Vavouranakis, Aris Androulakis, John Karabelas, Elli Stefanadis, Christodoulos Stefanadis, Ippokrateion Hospital, University of Athens, Athens, Greece Background: Patients (pts) with coronary artery disease and diabetes mellitus (DM) show increased systemic inﬂammatory activation. Thermography detects local inﬂammatory involvement as heat generation. The aim of this study was to detect if culprit lesions of pts with DM have increased thermal heterogeneity compared to non-diabetics. Methods: Among pts undergoing percutaneous coronary interventions, 45 with type 2 DM and 63 non-DM, matched for age, clinical syndrome, statin-aspirin intake and angiographic stenosis(%) were enrolled. In all pts coronary thermography (Medispes, ZWG, Switzerland) was performed and temperature difference (DT) between the atherosclerotic plaque and the proximal vessel wall was measured. Results: Pts with DM had increased thermal heterogeneity compared to non-DM (mean DT: 0.17±0.18ºC vs 0.09±0.02ºC, p=0.01) (Figure). Twenty one pts with DM and 24 non- DM pts suffered from acute coronary syndromes (ACS) (p=0.22). Pts with ACS and DM had higher DT than non-diabetics (mean DT: 0.29±0.31ºC vs 0.15±0.21ºC, p=0.02), same as in the chronic stable angina group (mean DT: 0.09±0.08ºC vs 0.05±0.04ºC, p=0.006). Conclusions: Increased thermal heterogeneity was observed in culprit lesions of pts with DM compared to non-DM pts. This study implies the need of an aggressive anti- inﬂammatory treatment in pts with coronary artery disease and type 2 DM. 2:30 p.m. 854-5 The Reduction of Inﬂammatory Biomarkers by Statin, Fibrate, and Combination Therapy Among Diabetic Patients With Mixed Dyslipidemia: The DIACOR Study Joseph B. Muhlestein, Heidi Thomas, Jonathan R. Jensen, Benjamin D. Horne, Richard B. Lanman, Farangis Lavasani, Robert L. Wolfert, Robert R. Pearson, Jeffrey L. Anderson, LDS Hospital, Salt Lake City, UT, University of Utah, Salt Lake City, UT Background: Diabetes (DM) and inﬂammation have been shown to inﬂuence the development of atherosclerosis. Statins and ﬁbrates reduce inﬂammatory (INF) biomarkers; however, the inﬂuence of a statin and ﬁbrate combination has yet to be elucidated. We assessed the effect of combination therapy on INF biomarkers in the DIACOR Study. Methods: Patients (pts) with type II diabetes and no history of coronary heart disease were considered for the study (N=498). Eligible pts underwent a 6-8 week washout period of all lipid-lowering medications and were enrolled if they demonstrated mixed dyslipidemia (having 2 out 3: LDL >100, triglycerides >200, or HDL <40). Pts were randomized to receive: simvastatin (S) 20 mg, fenoﬁbrate (F) 160 mg, or combination (C) of S 20 mg and F 160 mg. At 12 weeks post randomization, levels of high sensitivity C-reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured. Results: A total 300 (age = 61±11 yrs, males = 55%) were randomized. For each treatment arm, baseline levels of hsCRP were: F=2.69, S=2.75 and C=2.84 mg/L and of Lp-PLA2 were: F=366.1, S=360.8, and C=365.6 ng/ml. At 12-weeks, hsCRP in the over-all study population was signiﬁcantly reduced (-12.5%, p<0.0001) from baseline, but the effect did not differ among treatments (F=-18%, S=-17%, C=-13%). The effect was greatest among pts with baseline hsCRP levels above 2.0 mg/L (F = -24.0%, p=0.001; S= -22.2%, p=<0.0001; C = -18.2%, p=0.004). Likewise, Lp-PLA2 levels in the over-all study population were signiﬁcantly reduced (-28.8%, p=0.04) and the effect did not differ among treatments (F=-29%, S=-29%, C=-29%). This effect was also greatest among pts with baseline elevated Lp-PLA2 levels above the median of 329 ng/ml (F = -47%, p<0.0001; S = -45%, p=<0.0001; C = -42.1%, p<0.0001). Conclusion: S, F, and C therapy all lowered hsCRP and Lp-PLA2. Interestingly, C was no more effective than either form of monotherapy. These anti-INF effects were most pronounced among pts with elevated baseline levels. The potential for positive cardiovascular beneﬁts of therapy with both statins and ﬁbrates and their combination should be further evaluated in this high risk population. ACC_2006_8_VascularDisease.indd 377 1/4/06 5:21:38 PM 378A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n 2:45 p.m. 854-6 Effects of High-Dose Atorvastatin on HDL Anti- inﬂammatory/Pro-inﬂammatory Function and Disease Activity in Patients With Rheumatoid Arthritis: Results of the Statin Anti-Rheumatic Activity (SARA) Pilot Study Christina Charles, Dinesh Khanna, Mohamad Navab, Srinivasa Reddy, Alan M. Fogelman, Daniel E. Furst, Harold E. Paulus, Grace S. Park, Benjamin J. Ansell, David Geffen School of Medicine at UCLA, Los Angeles, CA Background: Patients with rheumatoid arthritis (RA) have a 2-3 fold increased risk of MI compared to the general population. Atorvastatin 40 mg daily has demonstrated mild anti-inﬂammatory effects in patients with RA. The current study examines the effects of atorvastatin 80 mg on the anti-/pro-inﬂammatory properties of HDL as well as clinical disease activity in patients with RA. Methods: 20 subjects with RA who did not require pharmacologic lipid lowering therapy per NCEP ATP-III guidelines were randomized in a double-blind placebo-controlled trial to receive 80 mg of atorvastatin (A) or placebo (P) daily in addition to stable anti-rheumatic drug therapy. Disease activity variables were followed over 12 weeks and the anti-/pro- inﬂammatory effects of HDL were measured by a cell free assay (CFA). Results: Baseline lipid levels (P: TC 201 ± 27 mg/dL, HDL-C 63 ± 10 mg/dL, LDL-C 118 ± 31 mg/dL, A: TC 191 ± 33 mg/dL, HDL-C 64 ± 17 mg/dL, LDL-C 110 ± 28 mg/ dL), CFA, and disease activity scale (DAS)-28 did not statistically differ between groups. However, highly-sensitive c-reactive protein (hs-CRP) levels were higher in the A group. After 12 weeks, 7 of 10 subjects that completed the A protocol had reduction in their CFA, while only 2 of 8 subjects that completed the P protocol decreased their CFA over the study period (p=0.06). There was a statistically signiﬁcant % reduction in hs-CRP at 3 weeks compared to baseline in the A compared to P group (p<0.04). There was also a trend for improvement in the DAS-28 (p=0.12) and the patient global assessment of disease activity (p=0.05) in the A group compared to the P group after 3 weeks of therapy. These improvements were not maintained at 12 weeks of therapy. Minor adverse events occurred with similar frequency in each treatment group. One subject from each group declined follow-up testing. Conclusions: In this population, HDL was rendered more anti-inﬂammatory by high-dose atorvastatin than placebo treatment. Atorvastatin reduced some but not all clinical and biochemical markers of RA activity, and was well-tolerated in patients with active arthritis receiving standard anti-rheumatic therapy. These results should be conﬁrmed by larger- scale clinical investigation. 3:00 p.m. 854-7 Lipoprotein-associated Phospholipase A2 (Lp-PLA2) in Chronic Kidney Disease: Results From the RRI-CKD Study Sanjay Rajagopalan, Mbabazi Kariisa, Robert Brook, Santo Dellegrottaglie, Alan Hinderliter, Xiaotong Zhang, Soyoung Chang, Margaret Kiser, George Eisele, Frederic Finkelstein, Nathan Levin, Martin Kuhlmann, Brenda Gillespie, Rajiv Saran, Zena and Michael A.Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY, University of Michigan, Ann Arbor, MI Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a calcium-insensitive lipase that is produced predominantly by macrophages in atherosclerotic plaque. The relationship between circulating levels of Lp-PLA2 and glomerular ﬁltration rate (GFR) is not known. We attempted to identify the correlates of Lp-PlA2 and understand its relationship to GFR in chronic kidney disease (CKD). Methods: The analysis included a cohort of 255 subjects (mean age 61 yrs, 52% male, 81% caucasian) of the Renal Research Institute (RRI)-CKD registry. This is an observational study (n=731 patients) of CKD (mean GFR=27±10 ml/min/1.73m2) at 4 academic centers. Plasma Lp-PLA2, C- reactive protein (CRP), interleukin (IL)-6 levels and nuclear magnetic resonance lipid sub- fractionation were determined at study entry. A simple correlation between demographic parameters and multiple linear regressions with Lp-PLA2 as outcome variable was carried out after adjusting for predictors such as age, gender, race, diabetes and lipid parameters. A patient-speciﬁc GFR slope was calculated using linear regression of GFR values measured over time in each patient. Results: Mean Lp-PlA2 levels, CRP and IL-6 levels were 218±70 ng/mL, 3.3±2.9 pg/mL and 4.8±7 mg/dL, respectively. While CRP values correlated with IL-6 (r=0.32, p<0.001), neither CRP nor IL-6 values correlated with Lp-PlA2 (p=0.38). Lp-PlA2 correlated with low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) particle number and all of the LDL and VLDL sub-fractions (p <0.05). There was no relationship between Lp-PlA2 level and GFR, GFR stage or microalbuminuria. Lp-PlA2 did not differ between subjects with positive/ﬂat GFR slope vs. those with negative GFR slope (p=0.64). On multivariate regression, signiﬁcant predictors of Lp-PlA2 levels were total cholesterol, serum calcium, albumin, LDL and VLDL particles concentration and all of the LDL and VLDL sub-fractions (p values <0.05 for all). Conclusion: CKD is characterized by systemic inﬂammation. There is no relationship between baseline GFR or GFR slope and Lp-PlA2 in this cohort of advanced CKD subjects. Lp-PlA2 levels strongly correlate with LDL and VLDL sub-fractions in CKD. 3:15 p.m. 854-8 C-Reactive Protein and Pro-Inﬂammatory Cytokines Are Elevated in Men With Erectile Dysfunction of Vascular Origin Charalambos Vlachopoulos, Nikolaos Ioakeimidis, Konstantinos Rokkas, Carmen Vassiliadou, Ioanna Dima, Marina Toutouza, Athanasios Askitis, Christodoulos Stefanadis, Athens Medical School, Hippokration Hospital, Athens, Greece Background: Erectile dysfunction (ED) may be the ﬁrst clinical manifestation of a generalized arterial disease. Chronic systemic inﬂammation plays a critical role in cardiovascular disease, and the inﬂammatory cascade is particularly important in the atherosclerotic process. The present study was undertaken to assess whether ED is associated with inﬂammatory markers/mediators, such as C-reactive protein (CRP), interleukin 6 (IL-6), interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α). Methods: A total of 121 men were studied: 39 men (aged 58±11 yrs) had ED without clinical evidence for coronary artery disease (CAD), 32 men (aged 61±8 yrs) had ED and CAD, 19 men (aged 59±11 yrs) had CAD and normal erectile function and 31 men (aged 57±6 yrs) were controls. CRP was measured by high sensitivity immunonephelometry. IL-6, TNF-α and IL-1β were measured using ELISA. Results: There was a progressive increase in hsCRP and IL-6 levels from controls to ED without CAD and CAD without ED, and to ED plus CAD patients (p<0.001, ﬁgure). There was also a signiﬁcant stepwise increase in inﬂammatory cytokines TNF-α and IL-1β from controls to ED without CAD and CAD without ED, and to ED plus CAD patients (p<0.001 and p<0.01, respectively). Conclusions: Circulating hsCRP levels and pro-inﬂammatory cytokines IL-6, TNF-α and IL-1β are associated with ED of vascular origin. This ﬁnding may be related to the pathophysiology of the disease and may have implications for the cardiovascular risk in these patients. ORAL CONTRIBUTIONS 855 Anticipated Agents: To Aggregate or Not Aggregate - That Is the Question Tuesday, March 14, 2006, 2:00 p.m.-3:30 p.m. Georgia World Congress Center, Room B407 2:00 p.m. 855-3 The Inﬂuence of Baseline Platelet Aggregation Response on Subsequent Inhibition of Aggregation Achieved With Clopidogrel or Prasugrel Joseph A. Jakubowski, Govinda J. Weerakkody, Kenneth J. Winters, John T. Brandt, Hideo Naganuma, Lars Wallentin, Eli Lilly and Company, Indianapolis, IN, Sankyo Co., Ltd., Tokyo, Japan Background: There is substantial inter-individual variability in the extent of inhibition of platelet aggregation (IPA) achieved with both aspirin and clopidogrel (C). It has been reported that markers of platelet activation (p-selectin) at baseline predict subsequent IPA with clopidogrel. We examined if baseline aggregation response was related to subsequent IPA following C or prasugrel (P) in cardiovascular (CV) patients. Methods: Fifty aspirin-treated patients with stable CV disease were randomly assigned to a loading dose (LD) of P (60 mg) or standard C LD (300 mg). Platelet aggregation was measured by light transmission aggregometry using 20 µM ADP. Maximal platelet aggregation (MPA) achieved during the aggregation assay was recorded both at baseline (BL) and at 6 hours after the LD. Results: As shown in the ﬁgure, there was variability in BL aggregation response (approximately 60-90% MPA) to 20 µM ADP. At 6 hours after a LD, the aggregation response was inhibited to varying degrees, resulting in a larger range of MPA (approximately 20- 90%). Regression analysis revealed signiﬁcant correlations (r) between BL and post-LD MPA for each treatment (C=0.64, p<0.001 and P=0.43, p<0.001). Conclusions: BL aggregation response inﬂuences subsequent level of IPA post LD. However, in general, regardless of BL reactivity, P has a greater antiplatelet effect than C. These observations add to our understanding of the variable response to thienopyridine antiplatelet agents. ACC_2006_8_VascularDisease.indd 378 1/4/06 5:21:39 PM JACC February 21, 2006 ABSTRACTS - Vascular Disease, Hypertension, and Prevention 379A Vascular D isease, H ypertension, and P revention 2:15 p.m. 855-4 Preprocedual Statin Administration Can Reduce Thrombosis Reaction in Both Acute Myocardial Infarction and Stable Angina - Histologic Evaluation Masami Nishino, Ken Matsuoka, Takahito Tamai, Tamaki Sawada, Hiroyasu Kato, Yasuyuki Egami, Ryu Shutta, Hitoshi Yamaguchi, Kenjiro Tanaka, Hideo Tanahashi, Jun Tanouchi, Yoshio Yamada, Division of Cardiology, Osaka Rosai Hospital, Sakai, Japan Background: It has been reported that statin therapy can reduce thrombosis as a pleiotropic effect, however there were few reports about this effect using histologic examination in human. . Methods: First, we studied consecutive 53 patients with acute myocardial infarction (AMI) who treated with thrombectomy catheter. According to microscopic analysis of the materials that retrieved from culprit lesions, we divided these patients into only thrombus (T) group and atheroma and thrombus (AT) group. Second, consecutive 45 stable angina (SP) patients with in-stent restenosis (ISR) who underwent directional coronary atherectomy were studied. According to histologic ﬁndings, we divided these patients into the group whose ISR tissue included thrombus and smooth muscle cell (SMC) (TS group) and the group whose ISR tissue included only SMC (S group). In both studies, before procedure, we evaluated serum markers including high sensitive C-reactive protein (hs- CRP), lipoprotein (a), total PAI-1, ﬁbrinogen, total cholesterol, triglyceride, high-density lipoprotein cholesterol, fasting blood sugar, and hemoglobin A1c. We also evaluated rate of classical coronary risk factors and preprocedual medications including statin, anticaogulation, angiotensin converting enzyme inhibitor / angiotensin II receptor blocker, Ca antagonist and β blocker. T group in AMIand TS group in SA were more associated with thrombosis reaction after procedures. Results: In AMI, rate of statin use in T group (n=25) was signiﬁcantly lower than AT group (n=28) (P<0.05), while there were no signiﬁcant differences of the other factors between the two groups. In SP, hs-CRP and PAI-1 in TS group (n=14) were signiﬁcant higher (both P<0.01) and rate of statin use in TS group was signiﬁcantly lower (P<0.05) than S group (n=31), while there were no signiﬁcant differences of the other factors between the two groups. Conclusions: According to histologic ﬁndings of aspiration materials and ISR tissue, preprocedural statin can reduce thrombosis reaction in both acute myocardial infarction and stable angina. 2:30 p.m. 855-5 Variability in the Recovery of Platelet Function After Discontinuation of Clopidogrel Therapy Matthew J. Price, Garrett B. Wong, Scripps Clinic, La Jolla, CA Background: Pre-operative clopidogrel (CLOP) use is associated with increased bleeding, reoperation, and prolonged hospital stay, and therefore CLOP is commonly discontinued 5 days prior to surgery. The time-course of recovery of platelet function after discontinuation is not well studied. Methods: Healthy volunteers (n=44) were treated with CLOP 75mg daily for a mean of 13.3 ± 5.4 days after a loading dose. Percent inhibition (PI) of platelet aggregation due to the ADP-mediated P2Y12 receptor was measured by the VerifyNow P2Y12 assay (Accumetrics) prior to initial exposure (D0), 24 hours after the last dose (D1), and on the 4 days thereafter (D2-D5). Results: While mean PI decreased signiﬁcantly each day of recovery, there were wide ranges of PI at each time point. On D1, the range of PI was 14% to 95%, on D2, 3% to 88%, on D3, 2.7% to 59%, on D4, 0 to 42.4% and on D5, 0 to 41.5%. A substantial proportion of subjects had low PI at each time point, and on D5, 2 subjects (5%) had persistent PI > 40%. Conclusions: The VerifyNow P2Y12 assay demonstrates that individual platelet inhibition varies widely after treatment with clopidogrel 75mg daily, and that there is substantial variability in the recovery of platelet function after therapy cessation. Further study is warranted to investigate the utility of point-of-care testing to identify patients on clopidogrel who require surgery and who may already have recovered platelet function prior to 5 days, or on the contrary, have persistent inhibition despite discontinuation. 2:45 p.m. 855-6 Increasing Concentrations of Prasugrel’s Active Metabolite Produce Increased Inhibition of Platelet Aggregation David S. Small, Christopher D. Payne, Lisa R. Ferguson-Sells, Nagy A. Farid, Hideo Naganuma, Christelle Darstein, Lars Wallentin, Kenneth J. Winters, Eli Lilly and Company, Indianapolis, IN, Sankyo Co., Ltd., Tokyo, Japan Background: Prasugrel (CS-747) is a novel thienopyridine P2Y12 ADP receptor antagonist with greater inhibition of platelet aggregation (IPA) than clopidogrel. This phase 1b study in aspirin-treated subjects with stable atherosclerotic disease characterized IPA and pharmacokinetics during 4 prasugrel dosing regimens. Methods: After a 7-day run-in on 325 mg aspirin, 101 subjects were randomly assigned to 1 of 5 oral dosing regimens of a loading dose (LD) and 27 days of maintenance dosing (MD): prasugrel, 40 mg LD/5 or 7.5 mg MD, 60 mg LD/10 or 15 mg MD; or standard clopidogrel therapy of 300 mg LD/75 mg MD. Prasugrel active metabolite (R-138727) concentrations were measured by LC/MS/MS and analyzed using noncompartmental pharmacokinetic methods. IPA to 20 µM ADP was determined by turbidometric aggregometry. Results: At 2 to 6 hours postdose, prasugrel LD 40 or 60 mg (mean IPA, 47%-62%) and MD 7.5,10, or 15 mg (mean IPA Day 28, 42%-63%) produced signiﬁcantly higher IPA versus clopidogrel LD (mean IPA, 23-24%, n=23) and MD (mean IPA day 28, 31-33%). R-138727 Cmax and AUC were dose-proportional across the LD and MD ranges. R-138727 after prasugrel LD (N) 40 mg (38) 60 mg (39) tmax (hr), median (range) 1.0 (0.5-4.0) 0.5 (0.5-4.0) Cmax (ng/mL); geometric mean (CV) 179 (82.0%) 223 (132%) AUC(0-tlast) (ng•h/mL) (CV) 221 (43.2%) 302 (70.0%) t1/2 (hr); geometric mean (range) 3.77 (1.87-21.4) 3.34 (1.32 - 8.44) %IPA, 4 hr; mean (95%CI) 52.8(48.8, 56.9) 60.9 (56.0, 65.8) R-138727 during prasugrel MD (N) 5 mg (19) 7.5 mg (19) 10 mg (19) 15 mg (20) Cmax (ng/mL); geometric mean (CV) 15.9 (92.0%) 35.6 (60.6%) 36.1 (78.9%) 66.0 (105%) AUCss (ng•h/mL) (CV) 22.3 (48.0%) 45.3 (37.1%) 52.8 (39.3%) 87.7 (48.7%) %IPA at 4 hr on day 28; mean (95%CI) 28.9 (18.8, 39.0) 47.1 (40.6, 53.7) 54.9 (47.2, 62.7) 62.1 (54.4, 69.8) ACC_2006_8_VascularDisease.indd 379 1/4/06 5:21:39 PM 380A ABSTRACTS - Vascular Disease, Hypertension, and Prevention JACC February 21, 2006 Va sc ul ar D is ea se , H yp er te ns io n, a nd P re ve nt io n Conclusions: In patients with stable atherosclerotic disease taking 325 mg aspirin per day, increasing concentrations of the prasugrel active metabolite produced increasing IPA. The IPA produced by once daily prasugrel doses of 7.5 mg and higher exceeds that produced by once daily doses of clopidogrel 75 mg. 3:00 p.m. 855-7 CYP2C19*2 Polymorphism Contributes to a Diminished Pharmacodynamic Response to Clopidogrel John T. Brandt, Sandra Kirkwood, Nitai Mukhopadhyay, Christopher D. Payne, Daniel Salazar, C. Steven Ernest, Kenneth J. Winters, Eli Lilly and Company, Indianapolis, IN, Sankyo Pharma Development, Edison, NJ Background: The individual pharmacodynamic response to standard doses of clopidogrel is variable and a diminished response has been reported to be associated with an increased risk of adverse events. Potential causes of this response heterogeneity include variation in absorption, concomitant medications, metabolism or interaction of active metabolite with P2Y12. We tested the hypothesis that a decreased pharmacodynamic response to clopidogrel is related to decreased generation of its active metabolite and associated with polymorphisms in cytochrome P450 (CYP) isoenzymes. Methods: The pharmacodynamic response to a 300 mg dose of clopidogrel was measured in 74 healthy subjects 4 and 24 hours post-dose using turbidometric platelet aggregation with 20 µM ADP as the agonist. Responders were deﬁned as subjects with ≥20% inhibition of platelet aggregation (IPA) at 4 and 24 hours post-dose. Clopidogrel active metabolite was measured by a validated liquid chromatography with tandem mass spectrometry detection method. Pharmacokinetic parameters were calculated by standard noncompartmental methods using WinNonlin Professional, with exposure expressed as area under the concentration curve (AUC) and maximal concentration (Cmax). Results: There was a signiﬁcant relationship between responder status and CYP2C19*2 (chi square p=0.015); 13 of 35 non-responders versus 5 of 39 responders were either heterozygous or homozygous for CYP2C19*2. Average IPA at 4 hours was signiﬁcantly lower for CYP2C19*2 carriers than homozygous wild type (17.2% versus 38.5%; p=0.001). The presence of CYP2C19*2 was associated with lower exposure to the active metabolite of clopidogrel, as measured by AUC (p=0.004) and Cmax (p=0.02). Conclusions: These results indicate that subjects with a CYP2C19*2 allele generate less active metabolite of clopidogrel and this is associated with a diminished pharmacodynamic response. Variation in CYP-mediated metabolism may be a signiﬁcant contributing factor to the previously reported inter-patient variability in the pharmacodynamic response to clopidogrel. 3:15 p.m. 855-8 High Dose Atorvastatin Does Not Impact the Efﬁcacy of Clopidogrel - A PROVE IT TIMI-22 Analysis Marc J. Schweiger, Gregory R. Giugliano, Amir Lotﬁ, Sabina A. Murphy, Christopher P. Cannon, The TIMI Study Group, Baystate Medical Center, Springﬁeld, MA, Brigham and Women’s Hospital, Boston, MA Background: Clopidogrel utilizes the cytochrome P450 3A4 pathway to convert prodrug to active metabolite. Atorvastatin , but not Pravastatin , utilizes this same pathway for drug metabolism. Thus, there has been theoretical concern that high dose atorvastatin might attenuate the efﬁcacy of clopidogrel, mediated by less platelet aggregation inhibition. There have been contradictory clinical reports suggesting clopidogrel is less efﬁcacious in patients taking atorvastatin. We hypothesized that there is no clinically meaningful interaction between atorvastatin and clopidogrel . Methods: We evaluated the 4161 patients with acute coronary syndrome randomized to Atorvastatin or Pravastatin in the Prove-It TIMI 22 trial. 3038 patients were on Clopidogrel at trial entry and 1123 were not. We utilized the Breslow-Day test to look for any interactions between patients taking the two statin drugs and Clopidogrel. Results: Outcomes measured at 30 days and two years showed no signiﬁcant difference in the combined endpoint of death or myocardial infarction (see table). Conclusions: There does not appear to be a clinically meaningful interaction nor reduction in efﬁcacy of clopidogrel in patients treated with high dose atrovastatin. 30 day and 2 year Outcomes Outcome Atorvastatin and Clopidogrel n=1542 Atorvastatin without Clopidogrel n=557 p-value Pravastatin and Clopidogrel n=1496 Pravastatin without Clopidogrel n=566 p-value Interaction p-value 30 day Death/MI 1.10 1.80 0.214 1.27 1.06 0.697 0.274 2 year Death/MI 7.66 9.92 0.149 9.71 10.72 0.3266 0.683 ACC_2006_8_VascularDisease.indd 380 1/4/06 5:21:39 PM

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